ES2265365T3 - PIPERIDINILOXI AND PIRROLIDINILOXIFENIL-OXAZOLIDINONA THAT HAVE ANTIBACTERIAL ACTIVITY. - Google Patents

Abstract

A compound of Formula I Formula I where R1 is where (a) R3 is H, alkyl, COR4, - (CH2) heteroaryl, -CHR5R6, - (CH2) taryl, -SO2NR5R6 or -SO2R9; (b) R4 is H, -OR5, alkyl, alkylaryl, - (CH2) taryl, - (CH2) theteroaryl, - (CH2) tOR5, - (CH2) tNR7R8, -CHR5R6 or -NR5R6 which eventually forms a cyclic amino derivative ; (c) R5 and R6 are independently H, alkyl, alkylaryl, haloaryl, - (CH2) taryl, - (CH2) t-heteroaryl or acyl; (d) R7 and R8 are independently H, alkyl, -COR9, -SO2R9 or -CO2R9, and (e) R9 is H, alkyl, aryl and alkylaryl; R2 is C (O) R9 or C (O) OR9; R2a is H or acyl, with the proviso that, when R3 is alkyl, - (CH2) taryl, - (CH2) theteroaryl or -CHR5R6, R2a is H; X is N or CH; Y is H, halogen, alkoxy or alkyl, and t is an integer from 0 to 4; or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof, wherein alkyl is C1-8 alkyl; heteroaryl is a cyclic aromatic radical of five to ten ring atoms, of which one ring atom is selected from S, O and N, 0-2 ring atoms are additional heteroatoms independently selected from S, O and N and the rest of the atoms of the ring are carbon; aryl is a carbocyclic aromatic radical selected from phenyl, 1-naphthyl or 2-naphthyl; Acyl is an organic radical having 2 to 6 carbon atoms derived from an organic acid by removal of the hydroxyl group, and alkoxy is an oxygen ether formed from alkyl.

Description

Piperidinyloxy and pyrrolidinyloxyphenyl-oxazolidinone having antibacterial activity

Field of the Invention

The present invention relates to the field of the piperidinyloxy-, pyrrolidinyloxy- and compounds acetidinyloxy-oxazolidinone that have activity antibacterial, with pharmaceutical compositions containing the compounds and with methods of treatment of bacterial infections With the compounds.

Background of the invention

Oxazolidinones have been identified in the last twenty years, as a new class of antibacterials that are active against numerous gram-positive organisms resistant to multiple drugs. Particularly problematic pathogens include methicillin- resistant Staphylococcus aureus ("MRSA"), vancomycin-resistant enterococci ("VRE") and penicillin and cephalosporin-resistant Streptococcus pneumoniae . As a class, oxazolidinones exhibit a unique mechanism of action. Studies have shown that these compounds selectively bind to the 50S ribosomal subunit and inhibit bacterial translation in the initiation phase of protein synthesis. Exemplary members of oxazolidinones are linezolid (see WO 95/07271) and eperezolid.

one

The following references relate to various oxazolidinone type compounds described as possessors of antibacterial activity:

Pat. USA No. 4,705,799 of W.A. Gregory describes derivatives of aminomethyloxooxazolidinylbenzene, including sulfides, sulfoxides, sulfones and sulfonamides, such as the (1) -N- [3- [4- (methylsulfinyl) phenyl] -2-oxooxazolidin-5-ylmethyl] acetamide.

Pat. USA No. 5,565,571 to Barbachyn et al. describes aril- and heteroarylphenyloxazolidinones.

Pat. USA No. 5,792,765 to Riedl et al. it is related to new oxazolidinones replaced.

Pat. USA No. 5,910,504 of Hutchinson describes phenyloxazolidinone compounds which have a heteroaromatic ring substitution containing nitrogen bound through one of the nitrogen atoms.

WO 93/09103 (Barbachyn et al.) Describes aryl- and heteroarylphenyloxazolidinones replaced.

WO 95/07271 (Barbachyn et al.) Describes oxazine and thiazine derivatives oxazolidinone

WO 98/54161 (Hester et al.) Provides oxazolidinone antibacterial agents which have a thiocarbonyl functionality.

Summary of the Invention

The invention provides new compounds piperidinyloxy, pyrrolidinyloxy and azetidinyloxy of Formula I

2

where

R_ {1} is

3

where

(to)

R 3 is H, alkyl, COR 4, - (CH 2) t heteroaryl, -CHR 5 R 6, - (CH 2) t aryl, -SO 2 NR 5 R 6 or -SO 2 R 9;

(b)

R 4 is H, -OR 5, alkyl, alkylaryl, - (CH 2) t aryl, - (CH 2) t heteroaryl, - (CH 2) t OR 5, - (CH 2) t NR 7 R 8, -CHR 5 R 6 or -NR5R6 that eventually forms an amino derivative cyclic;

(C)

R 5 and R 6 are independently H, alkyl, alkylaryl, haloaryl, - (CH 2) t aryl, - (CH 2) t -heteroaryl or acyl;

(d)

R 7 and R 8 are independently H, alkyl, -COR 9, -SO 2 R 9 or -CO_ {R} {9}, and

(and)

R 9 is H, alkyl, aryl and alkylaryl;

R2 is C (O) R9 or C (O) OR9;

R 2a is H or acyl, with the proviso that, when R 3 is alkyl, - (CH 2) t aryl, - (CH 2) t heteroaryl or -CHR 5 R 6, R 2a let H;

X is N or CH;

Y is H, halogen, alkoxy or alkyl, and

t is an integer from 0 to 4;

or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a salt pharmaceutically acceptable thereof,

where

alkyl is alkyl C 1-8;

heteroaryl is a cyclic aromatic radical of five to ten ring atoms, of which one ring atom is selected from S, O and N, 0-2 ring atoms are additional heteroatoms independently selected from S, O and N and the rest of the ring atoms are carbon;

aryl is a carbocyclic aromatic radical selected from phenyl, 1-naphthyl or 2-naphthyl;

acyl is an organic radical that has 2 to 6 carbon atoms derived from an organic acid by elimination of hydroxyl group, and

alkoxy is an oxygen ether formed from I rent.

The compounds of the above formula are useful. as antibacterial agents for the treatment of infections Bacterial in a subject, such as a human and an animal.

The present invention relates to a method of treating a subject who has a condition caused by, or the one that contributes, a bacterial infection, which consists of administer to said subject a therapeutically effective amount of the compound of Formula I.

The present invention also relates to a method of prevention of a subject suffering from a condition caused by, or to which it contributes, a bacterial infection, which it consists of administering to the subject an amount prophylactically Effective of the compound of Formula I.

Other objects and advantages will be apparent to those skilled in the art after a review of the description that It is given below.

Detailed description

In relation to the above description, certain Definitions apply as follows.

Unless otherwise indicated, under the standard nomenclature used throughout this description, the portion designated side chain terminal is described first, followed by the functionality adjacent to the junction point.

Unless otherwise specified, the terms "alkyl", "alkenyl" and "alkynyl", are already use alone or as part of a substituent group, include chains linear and branched from 1 to 8 carbon atoms, or any number within this range. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. The "alkoxy" radicals are oxygen ethers formed from linear or branched chain alkyl groups previously described. "Cycloalkyl" groups contain from 3 to 8 ring carbons and preferably 5 to 7 ring carbons. He alkyl group and alkoxy group can be independently substituted with one or more members of the group that includes, although without limitation, mono-, di-, tri- or per-halogen, alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, amino, amino substituted, OH, CN, mercapto, nitro and acyloxy C_ {1-8}.

The term "acyl," as used herein, whether used alone or as part of a substituent group, means a organic radical of 2 to 6 carbon atoms (branched chain or linear) derived from an organic acid by elimination of the group hydroxyl

The term "Ac", as used here, means acetyl.

The term "halo" or "halogen" It means fluorine, chlorine, bromine and iodine. (Mono-, di-, tri- and per-) haloalkyl is an alkyl radical substituted by substitution independent of the hydrogen atoms thereof with halogen.

"Arilo" or "Ar", whether used alone or as part of a substituent group, is an aromatic radical carbocyclic that includes, but is not limited to, phenyl, 1- or 2-naphthyl and the like. Aromatic radical carbocyclic may be substituted by independent substitution from 1 to 3 of the hydrogen atoms thereof with halogen, -OH, -CN, mercapto, nitro, amino, substituted amino, alkyl, -O-alkyl, -S-alkyl, -NH-alkyl, -N (alkyl) 2, (mono-, di-, tri- and per-) haloalkyl, formyl, -COR5, -COOR_ {5}, -CONHR_ {5}, -CONR_ {5} R6, -SOR_ {5}, -SO 2 R 5, -SO 2 NHR 5, -SO 2 NR 5 R 6, alkyl-COO, alkyl-CONH or carboxamide or a second aryl ring, where R 5 and R 6 are Define as before. As illustrative aryl radicals, they include, for example, phenyl, naphthyl, diphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxy-ethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamphenyl and the like. "Ph" or "PH" represents phenyl.

Whenever the term "alkyl", "acyl" or "aryl" or any of its prefix roots appears in a name of a substituent (e.g., aralkyl, dialkylamino), shall be construed to include those limitations given above for "alkyl", "acyl" and "arilo". The designated numbers of carbon atoms (e.g., C_ {1-8}) will independently refer to the number of carbon atoms in an alkyl or cycloalkyl moiety or at alkyl portion of a major substituent in which the alkyl It appears as its root prefix.

Whether used alone or as part of a substituent group, "heteroaryl" refers to a cyclic aromatic radical having five to ten ring atoms, of which a ring atom is selected from S, O and N, 0- 2 ring atoms are additional heteroatoms independently selected from S, O and N and the rest of the ring atoms are carbon. The radical being attached to the rest of the molecule by any of the ring atoms, for example pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl and the like The heteroaryl group may be substituted by independent substitution of 1 to 3 of the hydrogen atoms thereof with halogen, -OH, -CN, mercapto, nitro, amino, substituted amino, alkyl, -O-alkyl, -S-alkyl, -NH-alkyl, -N (alkyl) 2, (mono-, di-,
tri- and per-) haloalkyl, formyl, -COR 5, -COOR 5, -CONHR 5, -CONR 5 R 6, -SOR 5, -SO 2 R_ {5}, -SO 2 NHR 5, -SO 2 NR 5 R 6, alkyl-COO, alkyl-CONH or carboxamide, where R 5 and R 6 are as It has been defined here before. The heteroaryl can also be substituted with a mono-oxo to give 4-oxo-1H-quinoline and the like.

A "cyclic amino" derivative is a group cyclic containing nitrogen from 4 to 8 members where the others remaining members are selected from carbon, nitrogen, oxygen or sulfur, for example an azetidinyl group, a group pyrrolidinyl, a piperidinyl group, a morpholino group, piperazinyl or groups of the following formulas:

4

5

where p is 2 to 4 and q is 1 to Four.

"Heterocyclyl" or "heterocycle" is a single or fused ring system saturated or partially saturated from 3 to 8 members consisting of carbon atoms and of one to three heteroatoms selected from N, O and S. The group heterocyclyl can be attached to any heteroatom or atom of carbon, which results in the creation of a stable structure. Examples of heterocyclyl groups include, but are not limitation, pyridine, pyrimidine, oxazoline, pyrrole, imidazole, morpholine, furan, indole, benzofuran, pyrazole, pyrrolidine, piperidine and benzimidazole. The "heterocyclyl" or the "heterocycle" may be substituted with one or more groups independent, including, but not limited to, H, halogen, oxo, OH, alkyl, substituted alkyl, amino, substituted amino, carboxyl, alkylcarboxyl and alkoxy.

Unless otherwise specified, it it is intended that the definition of any substituent or variable in a particular location in a molecule is independent of its definitions elsewhere in that molecule. It is understood than substituents and substitution patterns over compounds of this invention can be selected by someone with ordinary knowledge in the art to obtain compounds that are chemically stable and that can be easily synthesized by techniques known in this field, as well as by methods exposed here.

The compounds of the present invention are asymmetric in the oxazolidinone ring at position 5 and, therefore both, they exist as optical antipodes. As such, all possible optical antipodes, enantiomers or diastereomers resulting from additional asymmetric centers that may exist in optical antipodes, racemates and racemic mixtures thereof are also part of this invention. The antipodes can be separated by methods known to those skilled in the art, such as, by example, fractional recrystallization of diastereomeric salts of enantiomerically pure acids. Alternatively, the antipodes they can be separated by chromatography on a Pirkle column.

The expression "pharmaceutically salt acceptable "represents free base salts that possess the desired pharmacological activity of the free base and that are not biologically or otherwise undesirable. These salts They can be derived from inorganic or organic acids. Are examples of inorganic acids hydrochloric acid, nitric acid, acid hydrobromic, sulfuric acid or phosphoric acid. Are examples of organic acids acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, acid citric, benzoic acid, cinnamic acid, mandelic acid, acid methanesulfonic acid, ethanesulfonic acid, acid p-toluenesulfonic acid, methylsulfonic acid, acid Salicylic and the like. Suitable salts are still those of bases inorganic or organic, such as KOH, NaOH, Ca (OH) 2, Al (OH) 3, piperidine, Morpholine, ethylamine, triethylamine and the like.

They are also included in the scope of the invention the hydrated forms of the compounds containing various amounts of water, for example hydrate forms, hemihydrate and sesquihydrate.

The term "subject" includes, without limitation, any artificially modified animal or animal. As a particular embodiment, the subject is a human.

The term "drug resistant" or "drug resistance" refers to the characteristics of a microbe to survive in the presence of an antimicrobial agent currently available, such as an antibiotic, at its concentration effective routine.

The compounds described herein invention possess antibacterial activity due to its new structure and are useful as antibacterial agents for Treatment of bacterial infections in humans and animals.

In particular, the compounds of Formula I where X is CH are embodiments of the present invention for said purposes.

The compounds of Formula I where R2 is C (O) R 9, where R 9 is as described before, they are particular embodiments of this invention.

More particularly, the compounds of Formula I where R 9 is H or alkyl are also embodiments of this invention.

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The compounds of Formula I where R 1 is

6

where R_ {3} is as it has been described above are other particular embodiments of this invention.

More specifically, the compounds of Formula I where R_ {2a} is H and R_ {3} is selected from -COR_ {4}, -SO 2 R 9 and (CH 2) t heteroaryl, where R 4, R 9 and t are as described above, they are embodiments of this invention.

Even more particularly, the compounds of Formula I where R_ {4} is selected from OR_ {5}, - (CH 2) t OR 5, alkyl, - (CH 2) t aryl and - (CH 2) t heteroaryl, where R 5 and t are as described above, they are embodiments of the invention.

The following are still other embodiments Particular of the present invention for said purposes:

(S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide,

(S) -N - [[3- [3-fluoro-4- {N - (α-hydroxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide,

(S) -N - [[3- [3-Fluoro-4- {N- (methanesulfonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide,

(S) -N - [[3- [3-Fluoro-4- {N- (methoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide,

(S) -N - [[3- [3-Fluoro-4- {N- (2-pyrimidinyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide,

(S) -N - [[3- [3-Fluoro-4- {N- (3-cyanobenzoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide,

(S) -N - [[3- [3-Fluoro-4- {N- (5-cyano-2-pyridyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide,

(S) -N - [[3- [3-Fluoro-4- {N- (2-thienylcarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide,

(S) -N - [[3- [3-Fluoro-4- {N - (α-hydroxyacetyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide  Y

(S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

Finally, the invention provides a procedure for preparing a compound of Formula Ia

7

where R_ {1} is a remainder of the formula

8

where:

R is selected from Boc, -CH (Ph) 2 or -COCH 2 OCH 2 Ph, n is 0, 1 or 2, m is 0 or 1 and R2, X and Y are as described above, whose procedure consists of:

(a) reacting a compound of Formula a with a compound of Formula a 'or a' 'to form a compound of Formula b;

9

(b) convert the compound of Formula b into a compound of Formula d;

(c) reacting the compound of Formula d with

10

to form a compound of Formula and;

eleven

(d) convert the compound of Formula e into a compound of Formula f;

(e) convert the compound of Formula f into a compound of Formula g;

12

(f) convert the compound of Formula g into a compound of Formula p, and

(g) convert the compound of Formula p into a compound of Formula Ia.

The compounds of Formula I can be prepared from easy starting materials availability, such as known oxazolidinone intermediates, according to synthetic methods well known in the art. The The following are representative procedures indicated in the Schemes I and II:

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Scheme I

13

According to Scheme I, when R is Boc, -CH (Ph) 2 or -COCH 2 OCH 2 Ph, R 11 is -COR 9 or -CO 2 R 9; R 'is any of the substituents on an aryl or heteroaryl group as previously described; R '' is selected from R_ {9} and -NR 5 R 6; R '' 'is selected from alkyl, alkyl substituted and -CHR 5 R 6; R 2a 'is alkyl eventually replaced; R '' '' is -SCH_ {3} or -OCH_ {3}; R_ {10} is -NR 9 R 9, R 9, -SR 9 or -NHR 9; n is 0, 1 or 2 and m is 0 or 1, and X, Y, R4, R5, R6, R9 and t are as has described before; a halonitrobenzene is added appropriately substituted such as that of Formula a 'or a halonitropyridine appropriately substituted such as that of Formula a '' to a compound of Formula a (all of which are marketed or can be easily prepared by known methods) in acetone, dimethylformamide (DMF) or tetrahydrofuran (THF). The mixture is treated with an appropriate base, such as t-butoxide potassium (KOtBu), to obtain the corresponding compound of Formula B The compound of Formula b can be reduced by corresponding compound of Formula c under appropriate conditions, such as H2, Pd / C and ethanol (EtOH) or NH4OCOH, Pd / C and methanol (MeOH). Compound c is treated with chloroformate of benzyl (CbzCl) in the presence of an appropriate base, such as cesium carbonate (CsCO3) in an appropriate solvent, such as THF, H2O or acetone, to obtain the corresponding compound of Formula d. Compound d is then treated with a base appropriate, such as nBuLi, followed by the addition of butyrate glycidyl, in an appropriate solvent, such as THF, to obtain the corresponding compound of Formula e. The compound of Formula e is treated with methanesulfonyl chloride (MsCl) and an appropriate base, such as triethylamine (NEt3), in an appropriate solvent, such as methylene chloride (CH 2 Cl 2). After the standard operations, sodium azide (NaN3) is then added to the mixture in an appropriate solvent, such as dimethylformamide (DMF), and heated to a preferred temperature range of 70 ° C to 90 ° C to obtain the corresponding compound of Formula f. It can reduce the compound of Formula f under appropriate conditions, such as H2 and Pd / C, in an appropriate solvent, such as acetate ethyl (EtOAc), or the compound of Formula f can be reduced using triphenylphosphine (PPh3) and THF / H2O, to obtain the corresponding compound of Formula g.

The compound of Formula g can be treated with a appropriate acylating agent, such as acetic anhydride (Ac2O) or acetyl chloride (AcCl), together with an appropriate base, such as pyridine or NEt3, to give the corresponding compound of Formula h. The compound of Formula g can also be treated with a appropriate imidate to give the corresponding compound of Formula I. The compound h where R is -CH (Ph) 2 can become the corresponding compound of Formula w by reaction with R 2a 'C (O) Cl in the presence of a base, just like ASD. Compounds j and k can be obtained from compounds h and i, respectively, by deprotection with acid trifluoroacetic acid (TFA) in an appropriate solvent, such as CH 2 Cl 2, or with Pd / C in an appropriate solvent, such as EtOH or EtOAc.

The compounds of the Formulas can be obtained o, q, r, s and u according to different routes as shown in the Scheme II:

Scheme II

14

The compound of Formula j or k can be treated with an appropriate alkylating agent represented by CIR '' 'in presence of an appropriate base, such as NEt_3, in a solvent appropriate, such as CH 2 Cl 2 or THF, to obtain the corresponding compound of Formula u. Alternatively, the compound of Formula j or k can be treated with a chloride of appropriate sulfonyl represented by R''SO2 Cl, such as MsCl, in the presence of an appropriate base, such as NEt_ {3}, in a appropriate solvent, such as CH2Cl2 or THF, to obtain the corresponding compound of Formula r. Still alternately, the compound of Formula j or k can be treated with an agent appropriate alkylating agent represented by

fifteen

where Z_ {1} and Z_ {2} are independently N or CH, in the presence of an appropriate base, such as NEt 3, in an appropriate solvent, such as CH 2 Cl 2 or THF, to obtain the corresponding compound of Formula q. In addition, the compound of Formula j or k can also be treated with an appropriate acylating agent represented by R 4 COCl, such as AcCl, in the presence of an appropriate base, such as NEt_ {3}, in a appropriate solvent, such as CH2Cl2 or THF, to obtain the corresponding compound of Formula o. In several cases, R_ {4} It contains a protected amine residue or protected alcohol. Behind the removal of the protective group, the amine or the resulting alcohol It can still be derivatized. The compounds of the Formulas o and r they can become compounds of Formulas v and s, respectively, by reaction with R 2a 'C (O) Cl in presence of a base, such as TORCH.

These compounds have antimicrobial activity against S. aureus, S. epidermidis, S. pneumoniae, E. faecalis, E. faecium, Moraxella catarrhalis and H. influenzae susceptible and drug resistant. These compounds are particularly useful against drug-resistant Gram-positive cocci, such as methicillin-resistant staphylococci and vancomycin-resistant enterococci. These compounds are useful in the treatment of community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital lung infections, bone and joint infections and of other bacterial infections.

The minimum inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art. The in vitro antimicrobial activity of the compounds was determined by the microdilution broth method according to the test method of the National Committee for Laboratory Standards (NCCLS). This method is described in NCCLS Document M7-A4, Vol. 17, No. 2, "Methods for Dilution Antimicrobial Susceptibility Test for Bacteria That Grow Aerobically - Fourth Edition", incorporated herein by reference.

In this method, serial dilutions are added to half of drug in Mueller-Hinton broth adjusted in cations to the wells of microdilution trays. They are getting ready test organisms by adjusting crop turbidity in active growing broth so that the final concentration of the test organism after adding it to the wells approximately 5 x 10 4 CFU / well.

After inoculation of the trays of microtiter, trays are incubated at 35 ° C for 16-20 hours and read later. The WCC is the lowest concentration of the test compound that completely inhibits the growth of the test organism. The amount of growth in The wells containing the test compound is compared to the amount of growth in the control wells of the growth (without test compound) used in each tray. How I know indicated in Table 1, the compounds of the present invention were studied against a variety of Gram pathogenic bacteria positive and gram negative, resulting in a spectrum of activities, from 1 to ≥ 128 \ mug / ml, depending on the studied organism

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TABLE 1 MIC values of some compounds of Formula I

16

17

This invention also relates to a method of treatment of bacterial or augmentation infections or potentiation of the activity of other antibacterial agents in warm-blooded animals, which consists of administering to animals a compound of the invention alone or in admixture with another antibacterial agent in the form of a medicament according to the invention.

When the compounds are used for Previous utility, can be combined with one or more brackets pharmaceutically acceptable, e.g., solvents, diluents and similar, and can be administered orally in forms such as tablets, capsules, dispersible powders, granules or suspensions that they contain, for example, about 0.5% to 5% agent suspensor, syrups containing, for example, approximately one 10% to 50% sugar and elixirs containing, for example, from about 20% to 50% ethanol and the like, or parenterally in the form of injectable solutions or suspensions sterile containing approximately 0.5% to 5% of suspending agent in an isotonic medium. These preparations Pharmaceuticals may contain, for example, approximately one 0.5% to approximately 90% of the active substance in combination with a support, more usually between 5% and 60% by weight.

Compositions for topical application can take the form of liquids, creams or gels, which contain a therapeutically effective concentration of a compound of the invention mixed with a dermatologically acceptable support.

When preparing the compositions in the form of oral dosage, any of the means can be used regular pharmacists As solid supports, they are included starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while, as liquid supports, are included sterile water, polyethylene glycols, non-ionic surfactants and oils edibles, such as corn, peanut and sesame oils, according to is appropriate for the nature of the active substance and the form Particular administration desired. Can be included advantageously adjuvants usually used in the preparation of pharmaceutical compositions, such as flavoring agents, coloring agents, preservatives and antioxidants, by example vitamin E, ascorbic acid, BHT and BHA.

Preferred pharmaceutical compositions from the point of view of ease of preparation and administration they are solid compositions, particularly tablets and capsules filled with solid or filled with liquid. The oral administration of the compounds. These active compounds they can also be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds can be prepared active as a free base or as a pharmacologically acceptable salt in water properly mixed with a surfactant, such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and their mixtures in oils. In ordinary storage and use conditions, these preparations may contain a preservative to avoid the microorganism growth

Pharmaceutical forms suitable for use injectable include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of solutions or sterile injectable dispersions. In all cases, the form it must be sterile and must be fluid to the extent that there is a Easy handling with syringe. It must be stable in the conditions of manufacturing and storage and should be preserved against the contaminating action of microorganisms such as bacteria and mushrooms. The support can be a solvent and a dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures of The same and vegetable oils.

The effective dosage of the active substance used may vary depending on the particular compound used, of the mode of administration and the severity of the condition in treatment. However, in general, results are obtained satisfactory when the compounds of the invention are administered at a daily dosage of approximately 0.1 mg / kg at approximately 400 mg / kg of the animal's body weight, preferably given in divided doses two to four times at day, in a form of sustained release. For more mammals large, the total daily dosage is approximately 0.07 g at 7.0 g, preferably about 100 mg to 1,000 mg. The Dosage forms suitable for internal use contain approximately 100 mg to 500 mg of the active substance in mixture intimate with a solid or liquid pharmaceutically acceptable support. This dosage regimen can be adjusted to obtain the optimal therapeutic response. For example, they can be administered several doses divided daily or can be reduced proportionally the dose as indicated by the requirements of The therapeutic situation.

The production of the previous compositions Pharmaceutical and medication is carried out by any method known in the art, for example mixing the active substance (s) with the diluent (s) to form a pharmaceutical composition (e.g., a granulate) and then forming the composition in the medicine (e.g., tablets)

The following examples describe in detail the chemical synthesis of representative compounds of the present invention. The procedures are illustrations and the invention has not if considered as limited by chemical reactions and conditions that express. No attempt has been made to optimize the yields obtained in these reactions and it will be obvious for a skilled in the art that variations in reaction times, temperatures, solvents and / or reagents could increase The returns.

Example 1 (S) -N - [[3- [3-Fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

18

N- ( t -Butoxycarbonyl) -4-piperidinol

To a solution of 25 g (247 mmol) of 4-piperidinol in 350 ml of dry tetrahydrofuran (THF) at 0 ° C was added dropwise 60.2 g (276 mmol) of di- t- butyl carbonate in 350 ml of Dry THF. The reaction was allowed to warm to room temperature (rt) and stirred overnight. The solvent was removed under reduced pressure, the resulting residue was dissolved in 700 ml of CH2Cl2 and the solution was extracted with H2O (1 x 400 ml), dried over MgSO4 , was filtered and rotary evaporated to obtain 45 g (91%) of N- ( t -butoxycarbonyl) -4-piperidinol as an oil, which slowly solidified to white crystals. 1 H NMR (CDCl 3) δ 3.75-3.96 (m, 3H), 2.92-3.13 (m, 2H), 1.80-1.93 (m, 4H) and 1.48 (s, 9H).

1- [N- ( t -Butoxycarbonyl) piperidinyl-4-oxy] -2-fluoro-4-nitrobenzene

To a solution of 740 mg (3.7 mmol) of N- ( t -butoxycarbonyl) -4-piperidinol in 10 ml of dry THF at 0 ° C, 4 ml (4.0 mmol) of 1 M KOtBu was added dropwise After stirring at 0 ° C for 0.5 h, 0.40 ml (3.6 mmol) of 3,4-difluoronitrobenzene was added and the reaction was heated to rt and stirred overnight. The reaction was poured into 100 ml of H2O and extracted with CH2Cl2 (3 x 100 ml). The combined aqueous layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation. The solid was then triturated with cold hexanes to obtain 1.1 g (89%) of 1- [N- ( t -butoxycarbonyl) piperidinyl-4-oxy] -2-fluoro-4-nitrobenzene as a light yellow solid; mp 88-90 ° C, MS (Cl) [M + Na] + 364.

1- [4- (N- t -Butoxycarbonyl) piperidinyl-4-oxy] -2-fluoro-4-aminobenzene

To 1.78 g (5.23 mmol) of 1- [N- ( t -butoxycarbonyl) piperidinyl-4-oxy] -2-fluoro-4-nitrobenzene in 100 ml of MeOH, 1.05 g (16, 6 mmol) of ammonium formate and 70 mg of 10% Pd / C and the reaction was heated at reflux under N2 for 2 h. The reaction was filtered through a celite pad and the filtrate was evaporated to obtain crude aniline as a golden oil. The material was used without further purification in the next step.

2-Fluoro-1- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} -4- (phenylmethoxycarbonylamino) benzene

At 1- [4- (Nt-butoxycarbonyl) piperidinyl-4-oxy] -2-fluoro-4-aminobenzene (5.23 mmol) in 150 ml of acetone: H2O 2: 1 at 0 ° C, were added 1.03 g (12.3 mmol) of NaHCO3 and 0.90 ml (6.30 mmol) of benzyl chloroformate. After stirring at rt for 6 h, the volatiles were evaporated, the residue was diluted with 300 ml of H2O and extracted with Et2O (3 x 150 ml). The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation. Chromatography on silica gel (20% EtOAc in hexanes) gave 2.06 g (89%) of 2-fluoro-1- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} -4- (phenylmethoxycarbonylamino) Benzene as a yellow waxy solid. 1 H NMR (CDCl 3) δ 7.3-7.4 (m, 6H), 6.9-7.0 (m, 2H), 6.60 (broad s, 1H), 4.3-4.4 (m, 1H), 3.7-3.8 (m, 2H), 3.2-3.3 (m, 2H), 1.8-2.0 (m, 2H ), 1.6-1.8 (m, 2H) and 1.48 (s, 9H).

(R) - [3- [3-Fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methanol

At 1.73 g (3.89 mmol) of 2-fluoro-1- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} -4- (phenylmethoxycarbonylamino) benzene in 25 ml of dry THF at -78 ° C, they added 2 ml (5.0 mmol) of 2.5 M N-BuLi and the reaction was stirred for 1 h. 0.71 ml (5.01 mmol) of (R) -glycidyl butyrate was then added by syringe and the reaction was heated to rt and stirred overnight. The reaction was carefully poured into 150 ml of NH4Cl sat. (aq.) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation. Chromatography on silica gel (40% EtOAc in hexanes to 70% EtOAc in hexanes) gave 1.15 g (72%) of (R) - [3- [3-fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methanol as a white solid; mp 110-111 ° C, MS (CI) [M + Na] + 433.5.

Methanesulfonate of (R) - [3- [3-fluoro-4- {N- ( t- butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl

At 1.03 g (2.51 mmol) of (R) - [3- [3-fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl ] methanol in 50 ml of CH 2 Cl 2 at 0 ° C was added 0.70 ml (5.02 mmol) of NEt 3 and 0.37 ml (4.78 mmol) of methanesulfonyl chloride. After stirring for 3 h at 0 ° C, the reaction was poured into 75 ml of H2O and extracted with CH2Cl2 (100 ml). The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation, to give 1.21 g (99%) of methanesulfonate of (R) - [ 3- [3-Fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl as a cream solid; mp 127-129 ° C, MS (CI) [M + H-Boc] + 389.2.

(R) - [3- [3-Fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide

To a solution of methanesulfonate of (R) - [3- [3-fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl (5.20 mmol) in 70 ml of dimethylformamide (DMF) 1.22 g (18.8 mmol) of sodium azide was added and the reaction was heated at 75 overnight. The reaction was then poured into 300 ml of H2O and extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with H2O (3 x 200 mL), dried over MgSO4, filtered and the solvent was removed by rotary evaporation to obtain 2.07 g (92%) of (R ) - [3- [3-Fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide as a beige solid. 1 H NMR (CDCl 3) δ 7.46 (dd, J = 12.9 and 2.7 Hz, 1H), 7.14 (dt, J = 8.9 and 1.4 Hz , 1H), 7.01 (t, J = 8.9 Hz, 1H), 4.7-4.8 (m, 1H), 4.3-4.4 (m, 1H), 4.05 ( t, J = 8.9 Hz, 1H), 3.83 (dd, J = 8.9 and 6.2 Hz, 1H), 3.7-3.8 (m, 2H), 3.71 (dd , J = 13.2 and 4.6 Hz, 1H), 3.59 (dd, J = 13.2 and 4.3 Hz, 1H), 3.2-3.3 (m, 2H), 1, 8-2.0 (m, 2H), 1.7-1.8 (m, 2H) and 1.47 (s, 9H).

(S) -N - [[3- [3-Fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (Compound 1)

To a solution of (R) - [3- [3-fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide (5.20 mmol) in 9 ml of dry THF 1.51 g (5.75 mmol) of triphenylphosphine was added and the reaction was stirred for 3 h at rt. Then 4.5 ml of H2O was added and the reaction was heated at 60 ° C for 4 h. The volatiles were evaporated and the residue was azeotroped with benzene (2 x 20 ml) to obtain the crude amine.

To a solution of this crude amine in 100 ml of EtOAc, 0.58 ml (6.15 mmol) of acetic anhydride and 1.2 ml (14.8 mmol) of pyridine were added and the reaction was stirred at rt overnight. . The reaction mixture was poured into 250 ml of H2O, extracted with EtOAc, dried over MgSO4, filtered and the solvent was removed under reduced pressure. Chromatography on silica gel (100% EtOAc to 5% MeOH in EtOAc) gave 1.85 g (79%) of (S) -N - [[3- [3-fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} -phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a white solid; mp 179-180 ° C, MS (CI) [M + Na] + 474.

Example 2 (S) -N - [[3- [3-Fluoro-4- {piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

19

To a solution of 1.94 g (4.30 mmol) of Compound 1 in 225 ml of CH2Cl2 was added 2.5 ml (32.5 mmol) of trifluoroacetic acid (TFA) and the reaction was stirred at rt for 6 h. Volatiles were evaporated under reduced pressure. Be the resulting oil (TFA salt) was dissolved in 100 ml of H2O, extracted with EtOAc (100 ml) and the aqueous layer was cooled to 0 ° C and basified with 1N NaOH. This solution was extracted with EtOAc (5 x 200 ml), the combined extracts were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure, to get (S) -N - [[3- [3-Fluoro-4- {piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide  like a light yellow crystal; m.p. 55-59 ° C, MS (CI) [M + H] + 352.

Example 3 (S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

twenty

To a suspension of Compound 2 (1.50 mmol) in 50 ml of CH2Cl2 was added 0.60 ml (4.3 mmol) of NEt3 and 0.25 ml (1.58 mmol) of benzyloxyacetyl chloride. After stirring for 18 h, the reaction was poured into 75 ml of H2O and extracted with CH2Cl2 (4 x 50 ml). The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. Chromatography on silica gel (5% MeOH in EtOAc) gave (S) -N - [[3- [3-fluoro-4- {N- (benzyloxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo -5-oxazolidinyl] methyl] acetamide as a white crystal. 1 H NMR (CDCl 3) δ 7.47 (dd, J = 12.9 and 2.5 Hz, 1H), 7.2-7.4 (m, 6H), 6.98 (t, J = 8.8 Hz, 1H), 6.24 (broad t, J = 6.1 Hz, 1H), 4.7-4.8 (m, 1H), 4.61 (s, 2H ), 4.4-4.5 (m, 1H), 4.20 (s, 2H), 4.02 (t, J = 9.0 Hz, 1H), 3.6-3.8 (m, 6H), 3.4-3.5 (m, 1H), 2.02 (s, 3H) and 1.8-1.9 (m, 4H).

Example 4 (S) -N - [[3- [3-Fluoro-4- {N - (α-hydroxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

twenty-one

To a solution of 540 mg (1.08 mmol) of Compound 3 in 50 ml of MeOH was added 503 mg of ammonium formate and a catalytic amount of 10% Pd / C and the reaction was heated at reflux overnight. The reaction was then filtered through a celite pad and the solvent was removed under reduced pressure. Chromatography on silica gel (2% to 10% MeOH in CH2Cl2) gave (S) -N - [[3- [3-fluoro-4- {N - (α-hydroxyacetamide) ) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetyl as a hygroscopic white foam (93%). 1 H NMR (CDCl 3) δ 7.49 (dd, J = 12.9 and 2.6 Hz, 1H), 7.09 (dd, J = 8.9 and 1.6 Hz , 1H), 7.00 (t, J = 8.9 Hz, 1H), 6.18 (broad t, J = 6.1 Hz, 1H), 4.7-4.8 (m, 1H), 4.51 (c, J = 4.6 Hz, 1H), 4.19 (s, 2H), 4.02 (t, J = 9.0 Hz, 1H), 3.5-3.8 (m , 7H), 3.20 (dt, J = 13.7 and 5.2 Hz, 1H), 2.03 (s, 3H) and 1.90 (m, 4H).

Example 5 (S) -N - [[3- [3-Fluoro-4- {N- (methoxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

22

To a solution of (S) -N - [[3- [3-fluoro-4- {piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (0.756
mmol) in 30 ml of EtOAc were added 1.0 ml (7.17 mmol) of NEt3 and methoxyacetyl chloride (0.875 mmol). The reaction was stirred at rt for 2.5 h, poured into 50 ml of H2O and extracted with EtOAc. The organic layer was washed with H2O, dried over MgSO4, filtered and the solvent removed by rotary evaporation, to obtain the impure amide. Chromatography on silica gel (2.5 to 10% MeOH in CH2Cl2) gave 101 mg (32%) of (S) -N - [[3- [3-fluoro-4- {N- (methoxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a beige foam. 1 H NMR (CDCl 3) δ 7.48 (dd, J = 12.9 and 2.5 Hz, 1H), 7.10 (m, 1H), 7.00 (t, J = 8.8 Hz, 1H), 6.00 (broad t, 1H), 4.77 (m, 1H), 4.46 (m, 1H), 4.13 (s, 2H), 4.03 ( t, J = 8.9 Hz, 1H), 3.5-3.8 (m, 6H), 3.44 (s, 3H), 3.43 (m, 1H), 2.03 (s, 3H ), and 1.7-1.9 (m, 4H).

Example 6 (S) -N - [[3- [3-Fluoro-4- {N- (methanesulfonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

2. 3

To a solution of 115 mg (0.33 mmol) of Compound 2 in 5 ml of CH 2 Cl 2 was added 0.05 ml (0.36 mmol) of NEt3 and 0.03 ml (0.39 mmol) of chloride methanesulfonyl. The reaction was stirred at rt for 22 h, poured in 50 ml of H2O and extracted with CH2Cl2. They were washed the organic layers combined with H2O, dried over MgSO4, filtered and solvent removed by evaporation rotary to obtain impure sulfonamide. The sulfonamide dissolving in EtOAc, washing with satd NaHCO3, drying over MgSO4 and removing the solvent under pressure reduced, to get (S) -N - [[3- [3-Fluoro-4- {N- (methanesulfonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide: m.p. 123-125 ° C, MS (CI) [M + H] + 430.

Example 7 (S) -N - [[3- [3-Fluoro-4- {N- (acetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

24

To a solution of 155 mg (0.44 mmol) of Compound 2 in 30 ml of CH2Cl2 was added 0.10 ml (0.72 mmol) of NEt3 and 0.05 ml ( 0.70 mmol) acetyl chloride. The reaction was stirred at rt for 18 h, poured into 50 ml of H2O and extracted with CH2Cl2. The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent removed by rotary evaporation to obtain the impure amide. The amide was purified by dissolving in EtOAc, washing with sat. NaHCO 3, drying over MgSO 4 and removing the solvent under reduced pressure, to obtain (S) -N - [[3- [3-fluoro-4- {N- (acetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide. 1 H NMR (CDCl 3) δ 7.47 (dd, J = 12.9 and 2.2 Hz, 1H), 7.06 (m, 2H), 6.97 (broad t, J = 8.8 Hz, 1H), 4.79 (m, 1H), 4.46 (m, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.6-3, 8 (m, 6H), 3.52 (m, 1H), 2.12 (s, 3H), 2.02 (s, 3H) and 1.88 (m, 4H).

Example 8 (S) -N - [[3- [3-Fluoro-4- {N- (methoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

25

To a solution of 201 mg (0.57 mmol) of Compound 2 in 50 ml of EtOAc was added 0.15 ml of NEt3 and 0.10 ml of methyl chloroformate. The reaction was stirred at rt for 20 h, poured into 50 ml of H2O and extracted with EtOAc. The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation to obtain 167 mg (72%) of (S) -N - [[3- [3-Fluoro-4- {N- (methoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a white solid. 1 H NMR (CDCl 3) δ 7.47 (m, 1H), 7.26 (m, 1H), 7.06 (m, 1H), 6.03 (m, 1H), 4.78 (m, 1H), 4.41 (m, 1H), 4.02 (t, J = 8.9 Hz, 1H), 3.71 (s, 3H), 3.6-3.7 (m, 5H), 3.41 (m, 2H), 2.02 (s, 3H), 1.89 (m, 2H) and 1.79 (m, 2H).

Example 9 (S) -N - [[3- [3-Fluoro-4- {N- (2-pyrimidinyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

26

To a solution of 176 mg (0.50 mmol) of Compound 2 in 7.5 ml of EtOH was added 0.23 ml of NEt3 and 61 mg (0.53 mmol) of 2-chloropyrimidine and the reflux reaction for 21 h. After cooling, the reaction in 50 ml of NaHCO 3 sat. and it was extracted with CH 2 Cl 2 (4 x 50 ml). The organic layers were washed combined with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation, to obtain 174 mg (81%) of (S) -N - [[3- [3-Fluoro-4- {N- (2-pyrimidinyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; m.p. 121-123 ° C, MS (CI) [M + H] + 430.

Example 10 (S) -N - [[3- [3-Fluoro-4- {N- (3-trifluoromethylbenzoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

27

To a solution of 101 mg (0.29 mmol) of Compound 2 in 10 ml of CH2Cl2 260 mg of AMBERLYST 21 Basic Resin and 1.0 ml (6.6 mmol) of chloride 3-trifluoromethylbenzoyl and the reaction was stirred for 3.5 h at rt. Then 2.4 g of P-trisamine and the reaction was stirred overnight. The reaction was filtered and the resin was washed with CH2Cl2. Be washed the combined organic layers with satd NaHCO3, se dried over MgSO4, filtered and the solvent removed by rotary evaporation, to obtain the crude amide. He crushed the amide with hexanes 3 times to obtain 100 mg (67%) of (S) -N - [[3- [3-Fluoro-4- {N- (3-trifluoromethylbenzoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide  like a white powder; m.p. 150-151 ° C, MS (CI) [M + H] + 524.

Example 11 (S) -N - [[3- [3-Fluoro-4- {N- (4-cyanobenzoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

28

To a solution of 51 mg (0.15 mmol) of Compound 2 in 7.5 ml of CH2Cl2 207 mg of Resin was added Basic AMBERLYST 21 and 116 mg (0.70 mmol) of chloride 4-cyanobenzoyl and the reaction was stirred for 18 h to ta. Then 250 mg of P-trisamine was added and The reaction was stirred for 20 h. The reaction was filtered and washed the resin with CH 2 Cl 2. The organic solvent was removed by rotary evaporation, to obtain 63 mg (91%) of (S) -N - [[3- [3-Fluoro-4- {N- (4-cyanobenzoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; m.p. 75-78 ° C, MS (CI) [M + H] + 481.

Example 12 (S) -N - [[3- [3-Fluoro-4- {N- (3-cyanobenzoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

29

To a solution of 75 mg (0.21 mmol) of Compound 2 in 7.5 ml of CH2Cl2 200 mg of Resin was added Basic AMBERLYST 21 and 128 mg (0.77 mmol) of chloride 3-cyanobenzoyl and the reaction was stirred for 18 h to ta. Then 300 mg of P-trisamine was added and The reaction was stirred for 20 h. The reaction was filtered and washed the resin with CH 2 Cl 2. The organic solvent was removed by rotary evaporation, to obtain 103 mg (100%) of (S) -N - [[3- [3-Fluoro-4- {N- (3-cyanobenzoyl) piperidinyl-4-oxy} -phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; m.p. 82-85 ° C, MS (CI) [M + H] + 481.

Example 13 (S) -N - [[3- [3-Fluoro-4- {N- (4-methoxybenzoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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30

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To a solution of 133 mg (0.29 mmol) of Compound 2 in 10 ml of CH2Cl2 350 mg of AMBERLYST Basic Resin 21 and 255 mg (1.49 mmol) of chloride p-anisoyl and the reaction was stirred for 3 h at rt. 1.0 g of P-trisamine was then added and stirred the reaction for 48 h. The reaction was filtered and the resin was washed with CH 2 Cl 2. The organic solvent was removed by rotary evaporation, to obtain (S) -N - [[3- [3-Fluoro-4- {N- (4-methoxybenzoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide Like a yellow crystal 1 H NMR (CDCl 3) δ 7.50 (m, 1H), 7.39 (m, 2H), 7.05 (m, 1H), 7.03 (m, 1H), 6.90 (m, 2H), 6.02 (m, 1H), 4.78 (m, 1H), 4.55 (m, 1H), 4.01 (m, 1H), 3.90 (s, 3H), 3.6-3.9 (m, 7H), 2.06 (s, 3H) and 1.95 (m, 4H).

Example 14 (S) -N - [[3- [3-Fluoro-4- {N- (5-cyano-2-pyridyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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31

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To a solution of 170 mg (0.48 mmol) of Compound 2 in 15 ml of EtOH was added 0.15 ml of NEt3 and
80 mg (0.58 mmol) of 2-chloropyridine-5-carbonitrile and the reaction was heated at 80 ° C for 72 h. After cooling, the reaction was poured into 50 ml of H2O and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and the solvent was evaporated by rotary evaporation, to obtain the crude product. Chromatography on silica gel (1% MeOH in EtOAc) gave 160 mg (73%) of (S) -N - [[3- [3-fluoro-4- {N- (5-cyano-2-pyridyl) ) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a yellow solid; mp 78-84 ° C, MS (CI) [M + H] +
454

Example 15 (S) -N - [[3- [3-Fluoro-4- {N - (α-phenylmethoxycarbonylaminoacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] - acetamide

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32

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To a solution of 266 mg (0.76 mmol) of Compound 2 in 15 ml of CH2Cl2 0.2 ml of NEt 3 and 188 mg (0.89 mmol) of acid fluoride phenylmethoxycarbonylglycine and the reaction was stirred at rt for 1.5 h. The reaction was then poured into 50 ml of NaHCO 3 sat. and extracted with CH 2 Cl 2. The organic layers were dried combined on MgSO4, filtered and solvent removed by rotary evaporation, to obtain 375 mg (91%) of (S) -N - [[3- [3-Fluoro-4- {N - (α-phenylmethoxycarbonylaminoacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide. 1 H NMR (CDCl 3) δ 7.50 (m, 1H), 7.39 (m, 5H), 7.11 (m, 1H), 7.03 (m, 1H), 6.24 (m, 1H), 5.87 (m, 1H), 5.15 (s, 2H), 4.75 (m, 1H), 4.52 (m, 1H), 4.06 (m, 3H), 3.6-3.8 (m, 6H), 3.37 (m, 1H), 2.10 (s, 3H) and 1.90 (m, 4H).

Example 16 (S) -N - [[3- [3-Fluoro-4- {N-? -Aminoacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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33

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A solution of 340 mg (0.62 mmol) of Compound 15 in 30 ml of EtOH was treated with 36 mg of 10% Pd / C, followed by hydrogenation at 50 psi overnight. The suspension was filtered through celite and the filtrate was evaporated under reduced pressure to obtain crude amine. Trituration of the crude solid with CHCl3 gave (S) -N - [[3- [3-fluoro-4- {N-? -Aminoacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5 -oxazolidinyl] methyl] acetamide; mp 142-146 ° C, MS (CI) [M + H] +
409

Example 17 (S) -N - [[3- [3-Fluoro-4- {N - (? -Methylsulfonylaminoacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] ace- tamida

3. 4

To a solution of 750 mg (4.28 mmol) of Boc-glycine in 25 ml of CH2Cl2 se 0.6 ml of DAST was added and the reaction was stirred at rt for 20 min. The reaction was then washed with cold H2O, the layer was dried organic over MgSO4, filtered and the solvent was removed at reduced pressure to obtain a brown solid. To a solution of this acid fluoride in 40 ml of CH2Cl2 was added 327 mg (0.70 mmol) of the TFA salt of Example 2 and 0.23 ml of NEt3 and The reaction was stirred at room temperature for 16 h. Was poured The reaction in 50 ml of satd NaHCO3 was extracted with CH2Cl2, washed with H2O, dried over MgSO4, dried filtered and the solvent was removed under reduced pressure to obtain 388 mg of the amide as a beige foam. At a solution of 0.70 mmol of this amide 0.55 ml of trifluoroacetic acid was added and The reaction was stirred at rt for 20 h. The volatiles were evaporated at reduced pressure to obtain a brown oil. To this TFA salt in 30 ml of CH2Cl2 0.23 ml of NEt3 and 0.07 were added ml (0.90 mmol) methanesulfonyl chloride and the reaction was stirred at rt for 18 h. The reaction was poured into 50 ml of NaHCO3 sat., extracted with CH2Cl2, washed with H2O, dried over MgSO4, filtered and the solvent was removed under pressure reduced, to obtain the crude sulfonamide. Purification by silica gel chromatography (5% MeOH in CH2Cl2) gave 109 mg (32%) of (S) -N - [[3- [3-Fluoro-4- {N - (? -Methylsulfonylaminoacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide  like a white foam; m.p. 78-82 ° C, MS (CI) [M + H] + 487.

Example 18 (S) -N - [[3- [3-Fluoro-4- {N - (α-N-acetylaminoacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

35

To a solution of 74 mg (0.63 mmol) of N-acetylglycine in 10 ml of CH2Cl2 is added 125 mg (0.65 mmol) of EDCI and the reaction was stirred at rt for 2 h. A solution of 304 mg (0.65 was then added mmol) of TFA salt of Example 2 and 0.15 ml (1.07 mmol) of NEt3 in 10 ml of CH 2 Cl 2 and the reaction was stirred at rt for 3 h. The reaction was poured into 10 ml of H2O and extracted with CH 2 Cl 2. The combined organic layers were dried over MgSO4, filtered and solvent removed by evaporation Rotary to obtain the crude product as a yellow oil. The silica gel chromatography (5% MeOH in CH2Cl2) gave 161 mg of (S) -N - [[3- [3-Fluoro-4- {N - (α-N-acetylaminoacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; m.p. 66-68 ° C, MS (CI) [M + H] + 451.

Example 19 (S) -N - [[3- [3-Fluoro-4- {N- (3-pyridoyl) piperidinyl-4-oxy} -phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

36

To a solution of 257 mg (0.55 mmol) of the salt TFA of Example 2 in 20 ml of CH2Cl2 0.4 ml was added (2.86 mmol) of NEt3 and 105 mg (0.59 mmol) of hydrochloride nicotinoyl chloride and the reaction was stirred at rt for 20 h. Be The reaction was poured into 50 ml of NaHCO3 and extracted with CH 2 Cl 2. The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent by rotary evaporation to obtain 161 mg (64%) of (S) -N - [[3- [3-Fluoro-4- {N- (3-pyridoyl) piperidinyl-4-oxy} -phenyl] -2-oxo-5-oxazolidinyl] -methyl] acetamide; m.p. 49-53 ° C, MS (CI) [M + H] + 457.

Example 20 (S) -N - [[3- [3-Fluoro-4- {N- (2-pyridoyl) piperidinyl-4-oxy} -phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

37

To a solution of 281 mg (0.60 mmol) of the salt TFA of Example 2 in 50 ml of CH 2 Cl 2 was added 0.3 ml of NEt 3 and 110 mg (0.62 mmol) of hydrochloride chloride pyridine-2-carbonyl and the reaction at rt for 72 h. The reaction was poured into 50 ml of NaHCO 3 sat. and extracted with CH2Cl2. They washed organic layers combined with H2O, dried over MgSO4, filtered and solvent removed by evaporation rotary to obtain 190 mg (69%) of (S) -N - [[3- [3-Fluoro-4- {N- (2-pyridoyl) piperidinyl-4-oxy} -phenyl] -2-oxo-5-oxazolidinyl] -methyl] acetamide; m.p. 55-58 ° C, MS (CI) [M + H] + 457.

Example 21 (S) -N - [[3- [3-Fluoro-4- {N- (4-pyridoyl) piperidinyl-4-oxy} -phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

38

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To a solution of 285 mg (0.61 mmol) of the salt TFA of Example 2 in 25 ml of CH2Cl2 0.5 ml was added of NEt 3 and 123 mg (0.69 mmol) of hydrochloride chloride isonicotinoyl and the reaction was stirred at rt for 20 h. Was poured the reaction in 50 ml of NaHCO 3 sat. and it was extracted with CH 2 Cl 2. The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent by rotary evaporation, to obtain 29 mg (10%) of (S) -N - [[3- [3-Fluoro-4- {N- (4-pyridoyl) -piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide Like a white foam 1 H NMR (CDCl 3) δ 8.73 (m, 2H), 7.50 (m, 1H), 7.41 (m, 2H), 7.06 (m, 2H), 6.08 (broad t, 1H), 4.69 (m, 1H), 4.54 (m, 1H), 4.04 (m, 1H), 3.90 (m, 2H), 3.6-3.8 (m, 4H), 3.34 (m, 1H), 2.03 (s, 3H), 1.97 (m, 2H) and 1.82 (m, 2H).

Example 22 (S) -N - [[3- [3-Fluoro-4- {N- (2-thienylcarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

39

To a solution of 251 mg (0.55 mmol) of the salt TFA of Example 2 in 25 ml of CH2Cl2 0.2 ml was added of NEt 3 and 0.07 ml (0.65 mmol) of chloride 2-thiophenecarbonyl and the reaction was stirred at rt for 72 h. The reaction was poured into 50 ml of NaHCO3 sat. Y it was extracted with CH2Cl2. The organic layers were washed combined with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation to obtain the gross product. The crude material was dissolved in 50 ml of CH 2 Cl 2, P-trisamine resin was added and The mixture was stirred for 2 h. The reaction was filtered and evaporated. the solvent under reduced pressure, to obtain (S) -N - [[3- [3-Fluoro-4- {N- (2-thienylcarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide; m.p. 48-51 ° C, MS (CI) [M + H] + 462.

Example 23 (S) -N - [[3- [3-Fluoro-4- {N-dimethylsulfamoyl) piperidin-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

40

To a solution of 179 mg (0.38 mmol) of the salt TFA of Example 2 in 20 ml of CH2Cl2 was added 0.12 ml of NEt 3 and 0.05 ml (0.47 mmol) of dimethylsulfamoyl chloride and The reaction was stirred at rt for 18 h. The reaction was poured into 50 ml of NaHCO 3 sat. and extracted with CH2Cl2. They were washed the organic layers combined with H2O, dried over MgSO4, filtered and solvent removed by evaporation Rotary to obtain the gross product. The oil crystallized raw from CH 2 Cl 2 / Et 2 O hot to obtain (S) -N - [[3- [3-Fluoro-4- {N-dimethylsulfamoyl) piperidin-4-oxy} phenyl] -2-oxo-5-oxazo-lidinyl] methyl] acetamide as a white solid; P.F. 132-134 ° C, MS (CI) [M + H] + 459.

Example 24 (S) -N - [[3- [3-Fluoro-4- {N- (dimethylcarbamoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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41

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To a solution of 229 mg (0.49 mmol) of the salt TFA of Example 2 in 20 ml of CH2Cl2 was added 0.15 ml (1.08 mmol) of NEt3 and 0.06 ml (0.65 mmol) of chloride dimethylcarbamoyl and the reaction was stirred at rt overnight. Be poured the reaction into 50 ml of satd NaHCO3. and it was extracted with CH 2 Cl 2. The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent by rotary evaporation, to obtain the crude product. The crude oil was crystallized from CH 2 Cl 2 / Et 2 O hot to get 175 mg (85%) of (S) -N - [[3- [3-Fluoro-4- {N- (dimethylcarbamoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a white solid; m.p. 120-131 ° C, MS (CI) [M + H] + 423.

Example 25 (S) -N - [[3- [3-Fluoro-4- {N- (4-morpholinocarbamoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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42

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To a solution of 205 mg (0.44 mmol) of the TFA salt of Example 2 in 25 ml of CH2Cl2 was added 0.13 ml of NEt3 and 0.06 ml (0, 51 mmol) of 4-morpholinecarbonyl chloride and the reaction was stirred for 4 h. The reaction was poured into 50 ml of NaHCO3 sat. and extracted with CH2Cl2. The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was triturated with Et2O and hexanes to obtain 198 mg (97%) of (S) -N - [[3- [3-fluoro-4- {N- (4-morpholinocarbamoyl) piperidinyl-4 -oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a white solid; mp 167-170 ° C, MS (CI)
[M + H] + 465.

Example 26 (S) -N - [[3- [3-Fluoro-4- {N- (4-pyridin-3-ylbutyryl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

43

4-Pyridin-3-ylbutyronitrile

To a solution of 0.66 ml (5.11 mmol) of 3-pyridinepropanol in 5 ml of CH2Cl2 at 0 ° C 0.62 ml (7.67 mmol) of pyridine and 0.47 ml (6.14 mmol) were added of methanesulfonyl chloride and the reaction was stirred for 4 h. Be concentrated the solution under reduced pressure and the mesylate was dissolved crude in 10 ml of DMF. To this solution was added 902 mg (18.41 mmol) of sodium cyanide and the reaction was stirred at 60 ° C for 3 days. The solution was then cooled, diluted with H2O (30 ml) and extracted with EtOAc (3 x 20 ml). The organic layers were washed combined with H2O, dried over MgSO4 and the solvent under reduced pressure to obtain a dark red oil. Be purified the crude nitrile by dissolving in EtOAc, washing with H2O, concentrating and filtering through a gel plug silica (5% MeOH in CH2Cl2) to obtain 425 mg (57%) of nitrile.

Acid 4-pyridin-3-yl-butyric

A solution of 425 mg was refluxed (2.91 mmol) of 4-pyridin-3-ylbutyronitrile in 15 ml conc. HCl for 8 h. The volatiles were evaporated at reduced pressure and the residue was dissolved in EtOH. When adding acetone and cool, a dark brown solid precipitated. The filtered and triturated with cold acetone to collect a total of 334 mg (69%) of the carboxylic acid.

Chloride 4-pyridin-3-ylbutyryl

To a solution of 247 mg (1.49 mmol) of acid 4-pyridin-3-yl-butyric in 10 ml of CH2Cl2 a drop of DMF and 2.3 ml were added (4.56 mmol) oxalyl chloride and the mixture was stirred at rt for 4 h. The volatiles were evaporated under reduced pressure and the Gross material in the following procedure.

(S) -N - [[3- [3-Fluoro-4- {N- (4-pyridin-3-ylbutyryl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (Compound 26)

To a solution of 597 mg (1.29 mmol) of the salt TFA of Example 2 in 20 ml of CH2Cl2 0.54 ml was added (3.86 mmol) of NEt3 at 0 ° C and the reaction was stirred for 30 min. heating up to ta. The solution was then cooled to 0 ° C, a solution of the above acid chloride in 20 ml was added CH 2 Cl 2 and the reaction was allowed to warm to rt. Be diluted the reaction with CH2Cl2, washed with NaHCO3 sat. (2 x 30 ml), washed with H2O (2 x 30 ml), dried over MgSO4, filtered and solvent removed by evaporation rotary, to obtain the raw product as a colored foam toasted. Purification by silica gel chromatography (10% of MeOH in EtOAc) gave 152 mg (24%) of (S) -N - [[3- [3-Fluoro-4- {N- (4-pyridin-3-ylbutyryl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide like a dirty white foam; m.p. 42-45 ° C, MS (CI) [M + H] + 499.

Example 27 (S) -N - [[3- [3-Fluoro-4- {N- (3-pyridin-3-ylpropionyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

44

3-Pyridinepropionyl Chloride

To a solution of 300 mg (1.99 mmol) of acid 3-pyridinepropionic in 10 ml of CH2Cl2 a drop of DMF and 2.3 ml (4.56 mmol) of chloride were added oxalyl and the mixture was stirred at rt for 4 h. The evaporated volatile under reduced pressure and the raw material was used in the following procedure

(S) -N - [[3- [3-Fluoro-4- {N- (3-pyridin-3-ylpropionyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (Compound 27)

To a solution of 917 mg (1.97 mmol) of the salt TFA of Example 2 in 20 ml of CH2Cl2 0.75 ml was added (5.41 mmol) of NEt3 at 0 ° C and the reaction was stirred for 30 min., heating up to ta. The solution was then cooled to 0 ° C, a solution of the above acid chloride in 20 ml of CH_ {Cl} {2} together with an additional equivalent of NEt_ {3} and The reaction was allowed to warm to rt and stirred for the night. The reaction was diluted with CH2Cl2, washed with NaHCO 3 sat. (2 x 30 ml), washed with H2O (2 x 30 ml), was dried over Na2SO4, filtered and solvent removed by rotary evaporation, to obtain the crude product as an oil dark orange Purification by silica gel chromatography (10% MeOH and 1% NEt 3 in EtOAc) gave 110 mg of (S) -N - [[3- [3-Fluoro-4- {N- (3-pyridin-3-ylpropionyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide like a foam; m.p. 45-47 ° C, MS (CI) [M + H] + 485.

Example 28 (S) -N - [[3- [3-Fluoro-4- {N- (3-phenylpropionyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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Four. Five

To a solution of 133 mg (0.27 mmol) of the salt TFA of Example 2 in 20 ml of CH2Cl2 was added 0.07 ml (0.53 mmol) of NEt3 and 0.04 ml (0.29 mmol) of chloride hydrocinamoyl and the reaction was allowed to warm to rt and stirred for 1 h. The reaction was diluted with CH2Cl2, washed with NaHCO 3 sat. (2 x 30 ml), washed with H2O (2 x 30 ml), dried over Na2SO4, filtered and the solvent by rotary evaporation to obtain the crude product Like a colorless oil. Purification by gel chromatography of Silica (10% MeOH in EtOAc) gave a clear crystal. Be crushed this material with EtOAc and hexanes to obtain (S) -N - [[3- [3-Fluoro-4- {N- (3-phenylpropionyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a white solid; MS (CI) [M + H] + 484.

Example 29 (S) -N - [[3- [4- {N- (Pyridin-2-ylmethoxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

46

(Pyridin-2-ylmethoxy) acetic acid t -butyl ester

To a solution of 0.5 ml (5.18 mmol) of 2-pyridylmethanol in 20 ml of THF at 0 ° C was added 270 mg (6.75 mmol) of NaH and the reaction was stirred for 0.25 h. 0.82 ml of t -butyl bromoacetate was then added and the reaction was heated to rt and stirred for 12 days. The reaction was poured into 100 ml of H 2 O, extracted with CH 2 Cl 2 (2 x 100 ml), the combined organic layers were washed with brine, dried over MgSO 4, dried. filtered and the solvent was removed under reduced pressure to obtain 1.16 g (61%) as a brown oil.

Acid (pyridin-2-ylmethoxy) acetic

A solution of 706 mg (3.16 mmol) of t -butyl ester of (pyridin-3-ylmethoxy) acetic acid and 1.5 ml of TFA in 25 ml of methylene chloride was stirred at room temperature for 20 h. Volatiles were evaporated to obtain crude acid.

(S) -N - [[3- [4- {N- (Pyridin-2-ylmethoxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (Compound 29)

At 460 mg (1.63 mmol) of acid (pyridin-2-ylmethoxy) acetic in 100 ml of CH 2 Cl 2, 405 mg (2.11 mmol) of EDCI, 634 mg (1.36 mmol) of the TFA salt of example 1 and 4.5 ml (32.2 mmol) of NEt3. The reaction was stirred at rt for 5 days. Be then the mixture was poured into 125 ml of H2O, extracted with CH 2 Cl 2, the organic layers were washed with brine, dried over MgSO4, filtered and the solvent removed by rotary evaporation Purification by gel chromatography of silica (5% MeOH in CH2Cl2) gave 403 mg (59%) of (S) -N - [[3- [4- {N- (pyridin-2-ylmethoxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide like a semi-solid yellow 1 H NMR (CDCl 3) δ 8.54 (m, 1H), 7.72 (m, 1H), 7.49 (m, 2H), 7.23 (m, 1H), 7.09 (m, 1H), 7.00 (m, 1H), 6.10 (m, 1H), 4.78 (m, 1H), 4.71 (s, 2H), 4.48 (m, 1H), 4.32 (s, 2H), 4.04 (m, 1H), 3.6-3.8 (m, 6H), 3.45 (m, 1H), 2.03 (s, 3H) and 1.83 (m, 4H).

Example 30 (S) -N - [[3- [4- {N- (Benzyloxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

47

1- [N- ( t -Butoxycarbonyl) piperidinyl-4-oxy] -4-nitrobenzene

To a solution of 10.0 g (49.68 mmol) of N- ( t -butoxycarbonyl) -4-piperidinol of example 1 in 125 ml of dry THF at 0 ° C. 74 ml (74.53 mmol) was added dropwise of 1M KOtBu After stirring at 0 ° C for 0.5 h, 5.27 ml (49.68 mmol) of p-fluoronitrobenzene was added and the reaction was heated to rt and stirred overnight. Volatiles were removed under reduced pressure and the reaction was diluted with 800 ml of H2O. The mixture was extracted with CH 2 Cl 2 (2 x 500 ml) and a brown solid was removed by filtration. The combined aqueous layers were washed with H2O, dried over MgSO4, filtered and the solvent removed by rotary evaporation, to obtain an orange solid. Purification by silica gel chromatography (hexane: EtOAc 3: 1) gave 6.98 g (44%) of 1- [N- ( t -butoxycarbonyl) piperidinyl-4-oxy] -4-nitrobenzene as a yellow solid Sure. An additional 3.20 g of product was extracted from the brown solid; MS (CI) [M + Na] + 345.

1- [4- (N- t -Butoxycarbonyl) piperidinyl-4-oxy] -4-aminobenzene

To 6.97 g (21.62 mmol) of 1- [N- ( t -butoxycarbonyl) piperidinyl-4-oxy] -4-nitrobenzene in 250 ml of MeOH, 6.81 g (108.1 mmol) of ammonium formate and a catalytic amount of 10% Pd / C and the reaction was heated at 50 ° C under N 2 for 5 h. The reaction was filtered through a pad of celite and the filtrate was evaporated, to obtain crude aniline as an orange oil. Material was used without further purification in the next step.

1- {N- ( t -Butoxycarbonyl) piperidinyl-4-oxy} -4- (phenylmethoxycarbonylamino) benzene

At 6.32 g (21.62 mmol) of 1- [4- (N- t -butoxycarbonyl) piperidinyl-4-oxy] -4-aminobenzene in 300 ml of acetone: H2O2: 1 at 0 ° C 4.50 g (52.97 mmol) of NaHCO3 and 3.30 ml (23.13 mmol) of benzyl chloroformate were added. The reaction was allowed to warm to rt and stirred overnight. The volatiles were then evaporated, the residue was diluted with 200 ml of H2O and extracted with Et2O (2 x 200 ml). The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation to obtain 8.62 g (93%) of 4- {N- ( t - butoxycarbonyl) piperidinyl-4-oxy} -1-phenylmethoxycarbonylamino) benzene as a pink solid; mp 107-108 ° C, MS (CI) [M + Na] + 449.

(R) - [3- [4- {N- ( t -Butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methanol

To 8.23 g (19.31 mmol) of 4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} -1- (phenylmethoxycarbonylamino) benzene in 300 ml of dry THF at -78 ° C 10.8 ml were added (27.03 mmol) of 2.5 M n -BuLi and the reaction was stirred for 1 h. Then 3.84 ml (27.03 mmol) of (R) -glycidyl butyrate was added by syringe and the reaction was heated to rt and stirred for 3 days. An additional 2 ml of 2.5 M n-BuLi was then added and the reaction was stirred for another day. The reaction was carefully poured into 150 ml of NH4Cl sat. (aq.) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation. Chromatography on silica gel (EtOAc) gave 4.34 g (57%) of (R) - [3- [4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl-2-oxo-5 -oxazolidinyl] methanol as a yellow solid; mp 110-112 ° C, MS (CI) [M + Na] + 415.

Methanesulfonate of (R) - [3- [4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl

At 4.23 g (10.79 mmol) of (R) - [3- [4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl-2-oxo-5-oxazolidinyl] methanol in 75 ml of CH 2 Cl 2 at 0 ° C, 3.0 ml (21.58 mmol) of NEt 3 and 1.2 ml (15.11 mmol) of methanesulfonyl chloride were added. The reaction was allowed to warm to rt over one hour and washed with H2O (2 x 50 mL), dried over MgSO4, filtered and the solvent removed by rotary evaporation, to obtain 5.0 g (99%) of (S) - [3- [4- {N- ( t- butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl methanesulfonate as a white foam

(R) - [3- [4- {N- ( t -Butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide

To a solution of 5.0 g (10.63 mmol) of methanesulfonate of (R) - [3- [4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy}
Phenyl] -2-oxo-5-oxazolidinyl] methyl in 100 ml of DMF was added 2.63 g (40.38 mmol) of sodium azide and the reaction was heated at 70 ° C overnight. The reaction was then poured into 200 ml of H2O and extracted with EtOAc (3 x 150 ml). The combined organic layers were washed with H2O (2 x 150 ml), dried over MgSO4, filtered and the solvent removed by rotary evaporation, to obtain 4.4 g (99% of (R ) - [3- [4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide as a yellow oil; MS (CI) [M + Na] +} 440.

(S) -N - [[3- [4- {N- ( t -Butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A solution of 4.48 g (10.73 mmol) of (R) - [3- [4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl was treated ] methylazide in 30 ml of EtOAc with a catalytic amount of 10% Pd / C, followed by hydrogenation at 50 psi for 20 h. 1.1 ml (12.88 mmol) of pyridine and 3.2 ml (34.34 mmol) of acetic anhydride were added to this mixture at 0 ° C. The reaction was stirred for 30 min. at 0 ° C and then heated to rt over 1 h. The reaction was filtered through celite, eluting with EtOAc. Volatiles were removed under reduced pressure and the yellow solid was dissolved in EtOAc and washed with H2O (3 x 100 mL). A white solid was removed by filtration. The organic layers were concentrated to an orange oil and crushed using EtOAc and hexanes, to obtain a white solid. The white solids were combined to obtain 1.48 g (31%) of (S) -N - [[3- [4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo- 5-oxazolidinyl] methyl] acetamide; mp 185-186 ° C, MS (CI) [M + Na] + 456.

(S) -N - [[3- [4- (Piperidinyl-4-oxy) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

To a solution of 1.48 g (3.41 mmol) of the above Boc-carbamate ((S) -N - [[3- [4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} phenyl] - 2-oxo-5-oxazolidinyl] methyl] acetamide) in 225 ml of CH2Cl2 2.6 ml (34.14 mmol) of trifluoroacetic acid was added and the reaction was stirred at rt for 2 h. The reaction was diluted with 50 ml of CH 2 Cl 2, washed with NaHCO 3 (2 x 100 ml), dried over MgSO 4, filtered and evaporated under reduced pressure, to obtain 980 mg (86%) of (S) -N - [[3- [4- (piperidinyl-4-oxy) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a yellow oil.

(S) -N - [[3- [4- {N- (Benzyloxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

At a suspension of 160 mg (0.48 mmol) of (S) -N - [[3- [4- (piperidinyl-4-oxy) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide in 20 ml of CH2Cl2 0.13 ml (0.96 mmol) of NEt 3 and 0.08 ml (0.53 mmol) of benzyloxyacetyl chloride. After stirring for 2 h, the reaction was poured into 75 ml of H 2 O and extracted with CH 2 Cl 2 (4 x 50 ml). They dried up the combined organic layers over MgSO4, filtered and evaporated under reduced pressure. Silica gel chromatography (10% MeOH in EtOAc) gave (S) -N - [[3- [4- {N- (benzyloxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide like a white foam; m.p. 53-55 ° C, MS (CI) [M + H] + 482.

Example 31 (S) -N - [[3- [4- {N - (α-Hydroxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

48

To a solution of 103 mg (0.21 mmol) of Compound 30 in 10 ml of MeOH was added 67 mg (1.07 mmol) of ammonium formate and a catalytic amount of 10% Pd / C and heated the reaction at 50 ° C for 3 days. Then the reaction through a celite pad, eluted with EtOAc and MeOH and the solvent was removed under reduced pressure, to obtain 56 mg (66%) of (S) -N - [[3- [4- {N - (α-hydroxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide like a white foam; MS (CI) [M + H] + 392.

Example 32 (S) -N - [[3- [4- {N- (Acetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

49

To a solution of 240 mg (0.72 mmol) of (S) -N - [[3- [4- (piperidinyl-4-oxy) phenyl] -2-oxo-5-oxazolidinyl] -methyl] acetamide in 20 ml of CH2Cl2 0.45 ml (3.24 mmol) of NEt 3 and 0.08 ml (1.08 mmol) of acetyl chloride and the mixture was stirred overnight reaction. The reaction was diluted with 50 ml of CH2Cl2, washed with H2O, dried over MgSO4, dried filtered and the solvent was removed by rotary evaporation to Get the raw product as a golden oil. Purification by silica gel chromatography (10% MeOH in EtOAc) gave 130 mg (50%) of (S) -N - [[3- [4- {N- (acetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a colorless oil; MS (CI) [M + Na] + 398.

Example 33 (S) -N - [[3- [4- {N- (Methanesulfonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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At a solution of 50 mg (0.15 mmol) of (S) -N - [[3- [4- (piperidinyl-4-oxy) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide in 20 ml of CH 2 Cl 2, 0.04 ml (0.30 mmol) of NEt 3 and 0.02 ml (0.21 mmol) of methanesulfonyl chloride and stirred the reaction overnight. The reaction was diluted with 10 ml. of CH 2 Cl 2, washed with H 2 O, dried over MgSO 4, filtered and the solvent removed by rotary evaporation, to Get the raw product as a golden oil. Purification by silica gel chromatography (10% MeOH in EtOAc) gave 40 mg (64%) of (S) -N - [[3- [4- {N- (methanesulfonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a white solid; MS (CI) [M + Na] + 434.

Example 34 (S) -N - [[3- [3-Fluoro-4- {N- ( t -butoxycarbonyl) pipeyridinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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N- ( t -Butoxycarbonyl) -3-piperidinol

To a solution of 10.0 g (72.67 mmol) of 3-hydroxypiperidine in 100 ml of dry THF 10.1 ml (72.67 mmol) of NEt3 and 15.86 g (72.67) mmol) of di- t- butyl carbonate in 100 ml of THF and the reaction was allowed to warm to rt and stirred overnight. The solvent was removed under reduced pressure, the resulting residue was dissolved in 300 ml of CH2Cl2 and the solution was extracted with H2O (2 x 200 ml), dried over MgSO4 , was filtered and subjected to rotary evaporation, to obtain 12.66 g (87%) of N- ( t -butoxycarbonyl) -3-piperidinol as an oil, which slowly solidified to a white solid.

1- [N- ( t -Butoxycarbonyl) piperidinyl-3-oxy] -2-fluoro-4-nitrobenzene

To a solution of 5.0 g (24.84 mmol) of N- ( t -butoxycarbonyl) -3-piperidinol in 75 ml of dry THF at 0 ° C was added dropwise 37 ml (37.26 mmol) of KOtBu 1 M. After stirring at 0 ° C for 0.5 h, 2.8 ml (24.84 mmol) of 3,4-difluoronitrobenzene was added and the reaction was heated to rt and stirred for 0.5 h. The volatiles were removed under reduced pressure and the residue was dissolved in 400 ml of H 2 O and extracted with CH 2 Cl 2 (2 x 300 ml). The combined aqueous layers were dried with MgSO4, filtered and the solvent was removed by rotary evaporation. Purification by silica gel chromatography (hexanes: EtOAc 3: 1) gave 5.94 g (70%) of 1- [N- ( t -butoxycarbonyl) piperidinyl-3-oxy] -2-fluoro-4-nitrobenzene ; MS (CI) [M + Na] + 363.

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1- [4- (N- t -Butoxycarbonyl) piperidinyl-3-oxy] -2-fluoro-4-aminobenzene

To 5.94 g (17.40 mmol) of 1- [N- ( t -butoxycarbonyl) piperidinyl-3-oxy] -2-fluoro-4-nitrobenzene in 200 ml of MeOH, 5.49 g (87.02 mmol) ) of ammonium formate and a catalytic amount of 10% Pd / C and the reaction was heated at 50 ° C under N 2 overnight. The reaction was filtered through a pad of celite and the filtrate was evaporated, to obtain crude aniline as an orange oil. The product was dissolved in 150 ml of EtOAc and washed with H2O (2 x 100), dried over MgSO4, filtered and the solvent removed under reduced pressure to obtain 4.98 g (92 %) as a light yellow oil. The material was used in the next step without further purification.

2-Fluoro-1- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} -4- (phenylmethoxycarbonylamino) benzene

At 4.98 g (16.08 mmol) of 1- [4- (N- t -butoxycarbonyl) piperidinyl-3-oxy] -2-fluoro-4-aminobenzene in 300 ml of acetone: H2O2 : 1 at 0 ° C, 3.31 g (39.40 mmol) of NaHCO 3 and 2.46 ml (17.20 mmol) of benzyl chloroformate were added. After stirring at rt overnight, the volatiles were evaporated, the residue was diluted with 200 ml of H2O and extracted with Et2O (3 x 150 ml). The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation. Chromatography on silica gel (EtOAc: Hexanes 2: 3) gave 5.30 g (75%) of 3-fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} -1- (phenylmethoxycarbonylamino) benzene as a white solid; mp 109-110 ° C, MS (CI) [M + Na] + 467.

(R) - [3- [3-Fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methanol

To 3.27 g (7.36 mmol) of 2-fluoro-1- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} -4- (phenylmethoxycarbonylamino) benzene in 150 ml of dry THF at -78 ° C was added 4.1 ml (10.31 mmol) of 2.5 M n-BuLi and the reaction was stirred for 1 h. 1.5 ml (10.31 mmol) of (R) -glycidyl butyrate was then added by syringe and the reaction was heated to rt and stirred overnight. The reaction was carefully poured into 100 ml of NH4Cl sat. (aq.) and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation. Chromatography on silica gel (EtOAc) gave 2.99 g (98%) of (R) - [3- [3-fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} phenyl] - 2-oxo-5-oxazo-lidinyl] methanol as a white foam; mp 48-50 ° C.

(R) - [3- [3-Fluoro-4- {N- ( t- butoxycarbonyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl methanesulfonate

At 1.32 g (3.22 mmol) of (R) - [3- [3-fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl ] methanol in 50 ml of CH 2 Cl 2 at 0 ° C was added 0.90 ml (6.44 mmol) of NEt 3 and 0.35 ml (4.51 mmol) of methanesulfonyl chloride. The reaction was allowed to warm to rt over 1 h and then washed with H2O (2 x 30 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. , to obtain 1.50 g (95%) of methanesulfonate of (R) - [3- [3-fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} phenyl] -2-oxo-5 -oxazolidinyl] methyl as a yellow foam.

(R) - [3- [3-Fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide

To a solution of 1.50 g (3.07 mmol) of methanesulfonate of (R) - [3- [3-fluoro-4- {N- ( t -butoxycarbonyl) -piperidinyl-3-oxy} phenyl] -2 -oxo-5-oxazolidinyl] methyl] acetamide in 60 ml of DMF was added 758 mg (11.66 mmol) of sodium azide and the reaction was heated at 75 ° C overnight. The reaction was then poured into 100 ml of H2O and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with H2O (3 x 200 mL), dried over MgSO4, filtered and the solvent was removed by rotary evaporation to obtain (R) - [3- [3-fluoro -4- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide as a foam.

(S) -N - [[3- [3-Fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

A solution of 1.34 g (3.07 mmol) of (R) - [3- [3-fluoro-4- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} phenyl] -2-oxo was treated -5-oxazolidinyl] methylazide in 30 ml of EtOAc with a catalytic amount of 10% Pd / C, followed by hydrogenation at 50 psi for 20 h. 0.3 ml (3.68 mmol) of pyridine and 0.93 ml (9.82 mmol) of acetic anhydride were added to this mixture at 0 ° C. The reaction was stirred for 30 min. at 0 ° C and then heated to rt over 1 h. The reaction was filtered through celite, eluting with EtOAc. Volatiles were removed under reduced pressure. Chromatography on silica gel (10% MeOH in EtOAc) gave (S) -N - [[3- [4- {N- ( t -butoxycarbonyl) piperidinyl-3-oxy} phenyl] -2-oxo-5 -oxazolidinyl] methyl] acetamide as a white solid; mp 60-63 ° C, MS (CI) [M + Na] + 474.

Example 35 (S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

52

(S) -N - [[3- [3-Fluoro-4- (piperidinyl-3-oxy) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

To a solution of 589 mg (1.31 mmol) of Compound 34 in 13 ml of CH2Cl2 was added 1.0 ml (13.1 mmol) of trifluoroacetic acid and the reaction was stirred at rt for 2 h. Volatiles were evaporated under reduced pressure to obtain (S) -N - [[3- [3-Fluoro-4- (piperidinyl-3-oxy) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide.

(S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) piperidinyl-3-oxy} phenyl-2-oxo-5-oxazolidinyl] methyl] acetamide

At a suspension of 303 mg (0.65 mmol) of (S) -N - [[3- [3-Fluoro-4- (piperidinyl-3-oxy) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide in 50 ml of CH2Cl2 0.27 ml (1.96 mmol) of NEt 3 and 0.11 ml (0.72 mmol) of benzyloxyacetyl chloride. After stirring for 1 h, the reaction was poured into 75 ml of H 2 O and extracted with CH 2 Cl 2 (4 x 50 ml). They dried up the combined organic layers over MgSO4, filtered and evaporated under reduced pressure, to obtain (S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) piperidinyl-3-oxy} phenyl-2-oxo-5-oxazolidinyl] methyl] acetamide like a foam; MS (CI) [M + H] + 500.

Example 36 (S) -N - [[3- [3-Fluoro-4- {N - (α-hydroxyacetyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

53

To a solution of 301 mg (0.60 mmol) of Compound 35 in 10 ml of MeOH was added 190 mg of formate of ammonium and a catalytic amount of 10% Pd / C and the reflux reaction overnight. The reaction was then filtered. through a pad of celite and the solvent was removed to reduced pressure Chromatography on silica gel (10% MeOH in EtOAc) gave 231 mg (82%) of (S) -N - [[3- [3-Fluoro-4- {N - (α-hydroxyacetyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide like a yellow foam; MS (CI) [M + H] + 410.

Example 37 (S) -N - [[3- [3-Fluoro-4- {N- (acetyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

54

At a solution of 100 mg (0.28 mmol) of (S) -N - [[3- [3-Fluoro-4- (piperidinyl-3-oxy) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide in 10 ml of CH2Cl2 0.12 ml (0.85 mmol) of NEt 3 and 0.03 ml (0.43 mmol) of acetyl chloride. He stirred the reaction at rt for 2 h, diluted with CH2Cl2, washed with H2O (2 x 100 ml), dried over MgSO4, filtered and removed the solvent by rotary evaporation, to obtain the amide impure Purification by silica gel chromatography (10% of MeOH in EtOAc) and trituration of the resulting oil with EtOAc and hexanes gave (S) -N - [[3- [3-Fluoro-4- {N- (acetyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide Like a solid

Example 38 (S) -N - [[3- [3-Fluoro-4- {N- (2-pyrimidinyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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To a solution of 151 mg (0.33 mmol) of (S) -N - [[3- (3-Fluoro-4- [piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide in 4 ml of EtOH 0.11 ml (0.82 mmol) of NEt3 and 39 were added mg (0.34 mmol) of 2-chloropyrimidine and the reflux reaction for 3 days. The reaction was cooled, poured in 15 ml of NaHCO 3 (sat.), it was extracted with CH 2 Cl 2, washed with H2O (2 x 100 ml), dried over MgSO4, filtered and the solvent was removed by rotary evaporation to obtain a orange oil The crude oil was triturated with EtOAc and Et2O to obtain 25 mg (23%) of (S) -N - [[3- [3-Fluoro-4- {N- (2-pyrimidinyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a light orange solid; m.p. 130-131 ° C, MS (CI) [M + H] + 429.

Example 39 (S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

56

N- (Benzyloxyacetyl) -3-pyrrolidinol

They were added to a solution of 4.4 ml (52.93 mmol) of 3-pyrrolidinol in 250 ml of CH 2 Cl 2 at 0 ° C 8.4 ml (60.26 mmol) of NEt 3 and 8.2 ml (51.97 mmol) of benzyloxyacetyl chloride. The reaction was stirred. for 3.5 h and then poured into 400 ml of H2O. It was extracted the reaction with CH 2 Cl 2, dried over MgSO 4, was filtered and subjected to rotary evaporation, to obtain 12.0 g (98%) of N- (benzyloxyacetyl) -3-pyrrolidinol Like a yellow oil

1- [N- (Benzyloxyacetyl) pyrrolidinyl-3-oxy] -2-fluoro-4-nitrobenzene

To a solution of 2.03 g (8.63 mmol) of N- (benzyloxyacetamide) -3-pyrrolidinol in 50 ml of THF at 0 ° C 10 ml (10.0 mmol) of drip were added KOtBu 1 M. After stirring at 0 ° C for 0.5 h, 0.96 was added ml (8.67 mmol) of 3,4-difluoronitrobenzene and the reaction was heated to rt and stirred overnight. The reaction in 100 ml of H2O and extracted by evaporation Rotary The solid was then recrystallized with EtOAc and hexanes, to obtain 2.49 g (77%) of 1- [N- (benzyloxyacetyl) pyrrolidinyl-3-oxy] -2-fluoro-4-nitrobenzene Like a solid

1- [4- (N-Benzyloxyacetyl) pyrrolidinyl-3-oxy] -2-fluoro-4-aminobenzene

At 1.61 g (4.31 mmol) of 1- [N- (benzyloxyacetamide) pyrrolidinyl-3-oxy] -2-fluoro-4-nitrobenzene in 50 ml of EtOH, 4.86 g (21.5 mmol) of SnCl2 was added and heated the reaction at 70 ° C for 2 h. The reaction was poured into ice water and extracted with EtOAc and CHCl3 (2 x 100 ml). Be The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure to obtain 880 mg (58%) of 1- [4- (N-benzyloxyacetamide) pyrrolidinyl-3-oxy] -2-fluoro-4-amino-benzene Like a yellow oil The material was used without further purification in the next stage.

2-Fluoro-1- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} -4- (phenylmethoxycarbonylamino) benzene

At 466 mg (2.73 mmol) of 1- [4- (N-benzyloxyacetyl) pyrrolidinyl-3-oxy] -2-fluoro-4-aminobenzene in 75 ml of ace-
tone: H 2 O 2: 1 at 0 ° C. 527 mg (6.27 mmol) of NaHCO 3 and 0.88 ml (2.56 mmol) of Cbz-Cl were added. The reaction was allowed to warm to rt and stirred overnight. The volatiles were evaporated, the residue was diluted with 200 ml of H2O and extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation. Silica gel chromatography (EtOAc) gave 473 mg (38%) of 3-fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} -1- (phenylmethoxycarbonylamino); MS (CI) [M + H] + 479.

(R) - [3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methanol

To 473 mg (0.99 mmol) of 2-fluoro-1- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} -4- (phenylmethoxycarbonylamino) benzene in 25 ml of dry THF at -78 ° C was added 0.55 ml (1.38 mmol) of 2.5 M n -BuLi and the reaction was heated to rt and stirred for 1 h. The solution was then cooled again to -78 ° C and 0.19 ml (1.38 mmol) of (R) -glycidyl butyrate was added by syringe and the reaction was heated to rt and stirred overnight. The reaction was carefully poured into 50 ml of NH4Cl sat. (aq.) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with H2O, dried over MgSO4, filtered and the solvent was removed by rotary evaporation. Chromatography on silica gel (0% to 10% MeOH in EtOAc) gave 107 mg (25%) of (R) - [3- [3-fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy } phenyl] -2-oxo-5-oxazolidinyl] methanol as a golden oil; MS (CI) [M + Na] + 445.

Methanesulfonate (R) - [3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl

At 107 mg (0.24 mmol) of (R) - [3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methanol in 50 ml of CH 2 Cl 2 at 0 ° C 0.07 ml (0.48 mmol) was added of NEt 3 and 0.03 ml (0.34 mmol) of methanesulfonyl chloride. After heating at rt and stirring for 1 h, the reaction with 10 ml of CH2Cl2, washed with H2O, was dried over MgSO4, filtered and solvent removed by rotary evaporation, to obtain methanesulfonate from (R) - [3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl; MS (CI) [M + H] + 523.

(R) - [3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide

To a solution of 2.22 g (4.25 mmol) of methanesulfonate (R) - [3- [3-Fluoro-4- {N- (benzyloxyacetyl) -pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl in 40 ml of DMF 1.05 g (16.13 mmol) of sodium azide were added and The reaction was heated at 75 overnight. Was poured then the reaction in 20 ml of H2O and extracted with EtOAc (3 x 100 ml) The combined organic layers were washed with H2O, dried over Na2SO4, filtered and the solvent by rotary evaporation to obtain 1.29 g (65%) of (R) - [3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide;  MS (CI) [M + H] + 471.

(S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (Compound 39)

To a solution of 1.29 g (2.74 mmol) of (R) - [3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide in 30 ml of MeOH 1.38 ml (13.71 mmol) of 1,3-propanedithiol and 1.91 ml (13.71 mmol) of NEt 3 and the reaction was stirred overnight at rt. They were added then 0.78 ml (8.23 mmol) of acetic anhydride and 1.33 ml (16.45 mmol) of pyridine and the reaction was stirred at rt for 3 h. Leaked the reaction through a vitrified funnel, rinsed with MeOH and It was concentrated under reduced pressure. The residue was then diluted with EtOAc, washed with H2O (3 x 100 ml), washed with brine, washed dried over Na2SO4 and the solvent was removed under pressure reduced, to obtain an orange oil. Purification by silica gel chromatography (10% MeOH in EtOAc) gave 1.02 g (77%) of (S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide like a white foam; m.p. 53-55 ° C, MS (CI) [M + H] + 486.

Example 40 (S) -N - [[3- [3-Fluoro-4- {N - (α-hydroxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

57

To a solution of 695 mg (1.43 mmol) of Compound 39 in 40 ml of MeOH was added 451 mg (7.17 mmol) of ammonium formate and a catalytic amount of 10% Pd / C and heated the reaction to reflux overnight. Leaked then the reaction through a celite pad and the solvent under reduced pressure. Trituration with EtOAc, MeOH and hexanes gave 363 mg (64%) of (S) -N - [[3- [3-fluoro-4- {N - (α-hydroxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide like a white powder; m.p. 97-99 ° C, MS (CI) [M + H] + 396.

Example 41 (5S) -3- [6- {N- ( t -Butoxycarbonyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one

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2- [N- ( t -Butoxycarbonyl) piperidinyl-4-oxy] -5-nitropyridine

To a solution of 15.23 g (75.7 mmol) of N- ( t -butoxycarbonyl) -4-piperidinol in 450 ml of THF at 0 ° C was added 126 ml (126 mmol) of KO t Bu and the reaction was stirred for 40 min. Then 10.0 g (63 mmol) of 2-chloro-5-nitropyridine were added and the reaction was heated to room temperature and stirred overnight. The reaction was diluted with H2O, extracted with Et2O, dried over MgSO4, filtered and the solvent was removed under reduced pressure to obtain the crude product as a black oil. Purification by silica gel chromatography (EtOAc: hexanes 1: 1) gave the desired product; MS (CI) [M + H] + 324.

2- [N- ( t -Butoxycarbonyl) piperidinyl-4-oxy] -5-aminopyridine

A solution of 280 mg (0.87 mmol) of 2- [N- ( t -butoxycarbonyl) piperidinyl-4-oxy] -5-nitropyridine in 30 ml of EtOH was treated with a catalytic amount of 10% Pd / C , followed by hydrogenation at 50 psi overnight. The suspension was filtered through celite and the filtrate was evaporated under reduced pressure to obtain the crude amine as a dark solid; MS (CI) [M + H] + 294.

2- {N- ( t -Butoxycarbonyl) piperidinyl-4-oxy} -5- (phenylmethoxycarbonylamino) pyridine

To a solution of 5.4 g (18.4 mmol) of 2- [N- ( t -butoxycarbonyl) piperidinyl-4-oxy] -5-aminopyridine in 300 ml of THF: H2O 1: 1 is they added 7.18 g (22.1 mmol) of cesium carbonate and 3.16 ml (22.1 mmol) of benzyl chloroformate and the reaction was stirred at rt overnight. The mixture was diluted with H2O, extracted with EtOAc, dried over MgSO4, filtered and the solvent removed under reduced pressure, to obtain a dark solid. Purification by silica gel chromatography (hexanes: EtOAc 4: 1) gave 6.5 g (83%) of the carbamate as a yellow solid; MS (CI) [M + H] + 428.

(R) - [3- (6- {N- ( t -Butoxycarbonyl) piperidinyl-4-oxy} pyridin-3-yl] -2-oxo-5-oxazolidinyl] methanol

A solution of 5.17 g (12.1 mmol) of 2- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} -5- (phenylmethoxycarboni-) was cooled
lamino) pyridine in 250 ml of THF at -78 ° C and 5.32 ml (13.3 mmol) of 2.5 M nBuLi was added and the solution was stirred for 1 h. Then 1.89 ml (13.3 mmol) of R-glycidyl butyrate was added and the reaction was allowed to warm to rt and stirred overnight. The reaction was stopped with H2O, extracted with Et2O, dried over MgSO4, filtered and the solvent was removed under reduced pressure, to obtain 4.22 g (88%) of the alcohol as a brown oil; MS (CI) [M + H] + 394.

Methanesulfonate of (R) - [3- [4- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} pyridin-3-yl] -2-oxo-5-oxazolidinyl] methyl

To a solution of 4.22 g (10.7 mmol) of (R) - [3- (6- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} pyridin-3-yl] -2-oxo- 5-oxazolidinyl] methanol in 100 ml of CH 2 Cl 2 at 0 ° C was added 2.99 ml (21.4 mmol) of NEt 3 and the reaction was stirred for 45 min. 16 ml (15.0 mmol) of methanesulfonyl chloride and the reaction was stirred at rt overnight, the reaction was stopped with H2O, extracted with CH2Cl2, dried over MgSO_ {4}, filtered and the solvent removed under reduced pressure, to obtain the mesylate as a brown solid.

(R) - [3- [4- {N- ( t -Butoxycarbonyl) piperidinyl-4-oxy} pyridin-3-yl] -2-oxo-5-oxazolidinyl] methylazide

To a methanesulfonate solution of (R) - [3- [6- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} pyridin-3-yl] -2-oxo-5-oxazolidinyl] methyl (10.7 mmol) in 100 ml of DMF 2.78 g (42.8 mmol) of sodium azide was added and the reaction was heated at 75 ° C for 5 h. The reaction was cooled and the solvent was removed under reduced pressure. The residue was diluted with H2O, extracted with EtOAc, dried over MgSO4, filtered and the solvent removed under reduced pressure, to obtain a brown oil, which was used crude in the next reaction.

(5S) -3- [6- {N- ( t -Butoxycarbonyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one (Compound 41)

A solution of 3.3 g (7.9 mmol) of (R) - [3- [6- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} pyridin-3-yl] -2-oxo was treated -5-oxazolidinyl] methylazide in 30 ml of EtOAc with a catalytic amount of 10% Pd / C, followed by hydrogenation at 50 psi overnight. The suspension was filtered through celite and the filtrate was evaporated under reduced pressure, to obtain crude amine as a dark solid. The crude reaction mixture was treated with 0.47 ml (5.8 mmol) of pyridine and 2.39 ml (25 mmol) of acetic anhydride and stirred overnight at rt. Volatiles were removed under reduced pressure, to obtain a brown oil. Purification by silica gel chromatography (5% MeOH in EtOAc) gave 1.7 g of (5S) -3- [6- {N- ( t -butoxycarbonyl) piperidinyl-4-oxy} pyridin-3-yl ] -5-methyl-acetamide-oxazolidin-2-one as a white foam; mp 99-101 ° C, MS (CI) [M + H] + 435.

Example 42 (5S) -3- [6- {N- (Benzyloxyacetyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one

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(S) -3- [6- {N- (Piperidinyl-4-oxy) pyridin-3-yl} -2-oxo-5-oxazolidinyl] methyl] acetamide

To a solution of 500 mg (1.1 mmol) of Compound 41 in 50 ml of CH2Cl2 0.88 ml (11.2 mmol) of trifluoroacetic acid and the reaction was stirred at rt for 3 days. The volatiles were removed under reduced pressure, to obtain the salt TFA as a brown oil.

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(5S) -3- [6- {N- (Benzyloxyacetyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one (Compound 42)

A solution of 99 mg (0.18 mmol) of (R) -3- [6- {N- (piperidinyl-4-oxy) pyridin-3-yl} -2-oxo-5-oxazolidinyl] methyl] acetamide in 20 ml of CH2Cl2 with 0.12 ml (0.88 mmol) of NEt3 and The reaction was stirred at rt for 30 min. 0.06 was then added ml (0.36 mmol) of benzoxyacetyl chloride and the reaction was stirred overnight. Then 100 mg of PS-Trisamine and the suspension was stirred for 30 min. The reaction was filtered, stopped with 10 ml of H2O, extracted with CH 2 Cl 2 (2 x 20 ml), dried over MgSO 4 and the solvent was removed by rotary evaporation, to obtain 31 mg from (5S) -3- [6- {N- (benzyloxyacetyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one like a semi-solid toasted color. 1 H NMR (CDCl 3) δ 8.13 (s, 1H), 7.98 (m, 1H), 7.35 (m, 5H), 6.72 (m, 1H), 6.59 (m, 1H), 5.25 (m, 1H), 4.82 (m, 1H), 4.61 (s, 2H), 4.24 (s, 2H), 3.90 (m, 1H), 3.77 (m, 2H), 3.70 (m, 1H), 3.68 (m, 2H), 3.54 (m, 1H), 3.41 (m, 1H), 2.08 (s, 3H), 2.05 (m, 2H) and 1.83 (m, 2H).

Example 43 (5S) -3- [6- {N- (Acetyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one

60

Compound 43 was prepared from 71 mg (0.13 mmol) of the TFA salt of Example 42, 0.09 ml (0.53 mol) of NEt 3 and 0.02 ml (0.26 mmol) of acetyl chloride as described described above, to obtain 20 mg of (5S) -3- [6- {N- (acetyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one Like a white semi-solid. 1 H NMR (CDCl 3) δ 8.14 (m, 1H), 7.95 (m, 1H), 6.77 (s, 1H), 6.76 (broad s, 1H), 5.25 (m, 1H), 4.83 (m, 1H), 4.06 (m, 1H), 3.91 (m, 1H), 3.80 (m, 1H), 3.68 (m, 3H), 3.4-3.6 (m, 2H), 2.15 (s, 3H), 2.04 (s, 3H), 2.02 (m, 2H) and 1.77 (m, 2H).

Example 44 (5S) -3- [6- {N- (Methanesulfonyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one

61

Compound 44 was prepared from 56 mg (0.10 mmol) of the TFA salt of Example 42, 0.07 ml (0.50 mmol) of NEt 3 and 0.02 ml (0.20 mmol) of methanesulfonyl chloride as has been described before, to obtain 17 mg of (5S) -3- [6- {N- (methanesulfonyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one as a white solid; m.p. 175-176 ° C, MS (CI) [M + H] + 413.

Example 45 (5S) -3- [6- {N- (4-Cyanobenzoyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one

62

Compound 45 was prepared from 39 mg (0.07 mmol) of the TFA salt of Example 42, 0.05 ml (0.35 mmol) of NEt 3 and 23 mg (0.14 mmol) of chloride of 4-cyanobenzoyl as described above, to obtain 30 mg of (5S) -3- [6- {N- (4-cyanobenzoyl) piperidinyl-4-oxi} pyridin-3-yl] -5-methylacetamide-oxazolidin -2-one as a white semi-solid. 1 H NMR (CDCl 3) δ 8.13 (m, 1H), 7.97 (m, 1H), 7.69 (m, 2H), 7.57 (m, 2H), 6.78 (m, 1H), 6.48 (broad t, 1H), 5.34 (m, 1H), 4.82 (m, 1H), 4.18 (m, 2H), 3.5- 3.8 (m, 5H), 3.37 (m, 1H), 2.03 (s, 3H), 1.97 (m, 2H) and 1.82
(m, 2H).

Example 46 (5S) -3- [6- {N- (Benzoyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one

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Compound 46 was prepared from 48 mg (0.09 mmol) of the TFA salt of Example 42, 0.06 ml (0.43 mmol) of NEt 3 and 0.02 ml (0.20 mmol) of benzoyl chloride as has been described above, to obtain 50 mg of (5S) -3- [6- {N- (benzoyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methyl-acetamide-oxazolidin-2-one as a yellow solid; m.p. 180-182 ° C, MS (CI) [M + H] + 439.

Example 47 (5S) -3- [6- {N- (3-Fluorobenzoyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one

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Compound 47 was prepared from 50 mg (0.12 mmol) of the TFA salt of Example 42, 0.08 ml (0.60 mmol) of NEt 3 and 0.03 ml (0.24 mmol) of chloride 3-fluorobenzoyl as described above, to get 20 mg of (5S) -3- [6- {N- (3-fluorobenzoyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one as a transparent oil; MS (CI) [M + H] + 457.

Example 48 (5S) -3- [6- {N- (3-Methoxybenzoyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one

65

Compound 48 was prepared from 50 mg (0.12 mmol) of the TFA salt of Example 42, 0.08 ml (0.60 mmol) of NEt 3 and 0.03 ml (0.24 mmol) of chloride 3-methoxybenzoyl as described above, to get 20 mg of (5S) -3- [6- {N- (3-methoxybenzoyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one as a yellow oil; MS (CI) [M + H] + 468.

Example 49 (5S) -3- [6- {N- (Dimethylcarbamoyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one

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Compound 49 was prepared from 50 mg (0.12 mmol) of the TFA salt of Example 42, 0.08 ml (0.60 mmol) of NEt 3 and 0.02 ml (0.24 mmol) of dimethylcarbamoyl chloride as described above, to obtain 17 mg of (5S) -3- [6- {N- (dimethylcarbamoyl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one as a white semi-solid; MS (CI) [M + H] + 406.

Example 50 (5S) -3- [6- {N- (2-Benzyloxycarbonyl-3-methylbutyryl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one

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To a solution of 36 mg (0.06 mmol) of the salt TFA of Example 42 in 20 ml of CH2Cl2 was added 32 mg (0.13 mmol) of Cbz-VAL-OH, 13 mg (0.07 mmol) of EDCI and 35 mg (0.25 mmol) of HOBT. He stirred the reaction to ta overnight. The solution was then washed with H2O, extracted with CH2Cl2, washed with NaHCO3 sat., dried over MgSO4 and concentrated, to obtain 10 mg of (5S) -3- [6- {N- (2-benzyloxycarbonyl-3-methylbutyryl) piperidinyl-4-oxy} pyridin-3-yl] -5-methylacetamide-oxazolidin-2-one As a transparent oil. 1 H NMR (CDCl 3) δ 8.10 (m, 1H), 7.99 (m, 1H), 7.37 (m, 5H), 6.76 (m, 1H), 6.20 (m, 1H), 5.33 (s, 2H), 5.19 (m, 1H), 5.11 (m, 1H), 4.82 (m, 1H), 4.08 (m, 1H), 3.79 (m, 2H), 3.5-3.7 (m, 4H), 3.25 (m, 1H), 2.97 (m, 1H), 2.13 (m, 2H), 2.06 (s, 3H), 1.84 (m, 2H) and 1.30 (s, 6H).

Example 51 (S) -N - [[3- [3-Fluoro-4- {N- (2-furoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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To a solution of 572 mg of TFA salt of Example 2 in 50 ml of CH2Cl2 1.2 ml of triethylamine was added (TEA) and 0.20 ml of 2-furanoyl chloride. It stirred the reaction for 18 hours under a nitrogen atmosphere. Be The reaction was poured into 100 ml of water and extracted. The layer was dried Organic over MgSO4, filtered and evaporated to an oil. Be crushed this one with hot ether to get (S) -N - [[3- [3-Fluoro-4- {N- (2-furoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a white solid; m.p. = 134-136 ° C; MS (CI) [M + H] + 446.

Example 52 (S) -N - [[3- [3-Fluoro-4- {N- (5-isoxazolylcarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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To 433 mg (3.83 mmol) of 5-isoxazolcarboxylic acid in 10 ml of CH2Cl2 was added 1 drop of DMF, followed by 2 ml of oxalyl chloride (2M in CH2Cl_ {2}, 4 mmol). After stirring for 0.5 hours, a solution of 895 mg (1.92 mol) of the TFA salt of Example 2 and 1 ml of TEA in 5 ml of CH 2 Cl 2 were added. The reaction was dried over MgSO4, filtered and evaporated. This was purified by column chromatography with 5% MeOH / CH2Cl2 as eluent, to obtain (S) -N - [[3- [3-fluoro-4- {N- (5-isoxazolylcarbonyl)] piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a white foam. 1 H NMR (CDCl 3) δ 8.31 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 12.9, 2.6 Hz, 1H), 7.08-7.12 (m, 1H), 7.01 (t, J = 8.8 Hz, 1H), 6.77 (d, J = 1.8 Hz, 1H), 6.04 (t , J = 6.0 Hz, 1H), 4.73-4.81 (m, 1H), 4.52-4.57 (m, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.56-3.95 (m, 7H), 2.03 (s, 3H), 1.75-2.00 (m, 4H). MS (CI) [M + H] + 447.

Example 53 (S) -N - [[3- [3-Fluoro-4- {N- (acetoxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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To 2.12 g (4.55 mmol) of the TFA salt of Example 2 in 150 ml of CH2Cl2, 5 ml of TEA was added. After Stir for 15 min., 0.62 (5.76 mmol) of chloride was added. acetoxyacetyl and the reaction was stirred for 2.5 h. Evaporated volatiles and the residue was chromatographed using MeOH 10% / CH 2 Cl 2 as eluent. It was isolated (S) -N - [[3- [3-Fluoro-4- {N- (acetoxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide  as a light beige solid; m.p. = 146-147.5 ° C, MS (CI) [M + H] + 452.

Example 54 (S) -N - [[3- [4- {N- (Pyridin-4-ylmethoxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide

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(S) -N - [[3- [4- {N- (Chloroacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide

A solution of 4.19 g (9.00 mmol) of TFA salt of Example 2 and 3 ml of TEA in 125 ml of CH 2 Cl 2 drip to 0.75 ml of chloroacetyl chloride (9.42 mmol) in 100 ml of CH 2 Cl 2. After stirring at room temperature for 2 h, the reaction was poured into 300 ml of water and extracted. The organic layer was dried over MgSO4, filtered and evaporated to get (S) -N - [[3- [4- {N- (chloroacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide As a viscous oil.

(S) -N - [[3- [4- {N- (Pyridin-4-ylmethoxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide (Compound 54)

To 101.1 mg of NaH (60% in oil, 2.53 mmol) in 5 ml of anhydrous THF at 0 ° C, 265 mg (2.43 mmol) of pyridine-4-methanol in 5 ml of was added dropwise THF anhydrous. After stirring for 15 min., 503 mg (1.18 mmol) of (S) -N - [[3- [4- {N- (chloroacetyl) piperidinyl-4-oxy} phenyl] -2-oxo was added -5-oxazolidinyl] methylacetamide in 5 ml of anhydrous THF. The reaction was stirred at room temperature for 16 h and then poured into 125 ml of water. This was extracted with 3 x 100 ml of CH2Cl2. The combined organic layers were dried over MgSO4, filtered and evaporated. Pure (S) -N - [[3- [4- {N- (pyridin-4-ylmethoxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide was obtained, obtained by chromatography using MeOH 5% / CH 2 Cl 2, as a white foam. 1 H NMR (CDCl 3) δ 8.59 (d, J = 5.9 Hz, 2H), 7.47 (dd, J = 12.9, 2.6 Hz, 1H), 7.28 (d, J = 5.9 Hz, 2H), 7.07-7.11 (m, 1H), 6.99 (t, J = 8.8 Hz, 1H), 5.91-5 , 94 (m, 1H), 4.72-4.79 (m, 1H), 4.65 (s, 2H), 4.45-4.49 (m, 1H), 4.26 (s, 2H ), 4.02 (t, J = 8.9 Hz, 1H), 3.40-3.78 (m, 7H), 2.02 (s, 3H), 1.85-1.95 (m, 4H); MS (CI) [M + H] + 501.

Example 55 (S) -N - [[3- [4- {N- (Pyridin-3-ylmethoxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide

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To 117 mg of NaH (60% in oil, 2.93 mmol) in 5 ml of anhydrous THF at 0 ° C 0.24 ml (2.47 mmol) of pyridine-3-methanol in 5 ml of THF was added dropwise . After stirring for 15 minutes, 523 mg (1.22 mmol) of chloroacetamide of Example 54 in 5 ml of anhydrous THF was added in one portion. The reaction was heated to room temperature and stirred for 72 hours. The reaction was poured into 50 ml of water and extracted with 3 x 75 ml of CH2Cl2. The combined organic layers were dried over MgSO4, filtered and evaporated. Chromatography with 3% MeOH / CH 2 Cl 2 gave (S) -N - [[3- [4- {N- (pyridin-3-ylmethoxyacetyl) piperidinyl-4-oxy} phenyl] -2- oxo-5-oxazolidinyl] -methylacetamide as a transparent crystal. 1 H NMR (CDCl 3) δ 8.56-8.60 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 13.0, 2.6 Hz, 1H), 7.30 (dd, J = 7.8, 5.1 Hz, 1H), 7.08 (dd, J = 8.9, 1.6 Hz, 1H), 6.99 (t, J = 8.9 Hz, 1H), 6.02 (t, J = 6.2 Hz, 1H), 4.70-4.78 (m, 1H), 4, 64 (s, 2H), 4.43-4.47 (m, 1H), 4.24 (s, 2H), 4.02 (t, J = 8.9 Hz, 1H), 3.57-3 , 78 (m, 6H), 3.35-3.45 (m, 1H), 2.02 (s, 3H), 1.80-1.96 (m, 4H). MS (CI) [M + H] + 501.

Example 56 (S) -N - [[3- [4- {N- (Morpholinoacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide

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To 415 mg (0.97 mmol) of chloroacetamide of Example 54 in 15 ml of THF was added 0.25 ml (2.87 mmol) of morpholine. The reaction was stirred for 72 hours at room temperature, poured into 50 ml of water and extracted with 3 x 50 ml of CH2Cl2. The combined organic layers were washed with water, dried over MgSO4, filtered and evaporated. (S) -N - [[3- [4- {N- (morpholinoacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide was obtained as a clear crystal after chromatography (MeOH 3 % / CH 2 Cl 2). 1 H NMR (CDCl 3) δ 7.47 (dd, J = 13.0, 2.6 Hz, 1H), 7.07-7.11 (m, 1H), 7.00 (t, J = 8.8 Hz, 1H), 5.93 (broad t, J = 6.1 Hz, 1H), 4.73-4.79 (m, 1H), 4.44-4.78 (m, 1H), 4.02 (t, J = 9.0 Hz, 1H), 3.51-3.85 (m, 11H), 3.20 (s, 2H), 2.47-2, 51 (m, 4H), 2.03 (s, 3H), 1.81-1.96 (m, 4H). MS (CI) [M + H] + 479.

Example 57 (S) -N - [[3- [3-Fluoro-4- {N- (methanesulfonyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

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1- [N- (Diphenylmethyl) azetidinyl-3-oxy] -2-fluoro-4-nitrobenzene

At 5.40 g (22.56 mmol) of N- (diphenylmethyl) azetidin-4-ol in 200 ml of THF at 0 ° C 30 ml of KOtBu (1 M in THF, 30 were added mmol). After stirring for 0.5 h, 2.5 ml (22.58 were added mmol) of 3,4-difluoronitrobenzene. It warmed up reaction to room temperature and stirred for 18 h. After evaporation of THF, the residue was partitioned between 300 ml of water and 250 ml of CH 2 Cl 2. The aqueous layer was washed with Additional CH2Cl2. The organic layers were dried combined on MgSO4, filtered and evaporated. The Chromatography with 15% EtOAc / hexanes gave 1- [N- (diphenylmethyl) -azetidinyl-3-oxy] -2-fluoro-4-nitrobenzene pure as a golden viscous oil. 1 H NMR (CDCl 3) δ 7.96-8.01 (m, 2H), 7.16-7.47 (m, 10H), 6.72-6.80 (m, 1H), 4.88-5.00 (m, 1H), 4.94 (s, 1H), 3.70-3.81 (m, 2H), 3.17-3.27 (m, 2H). MS (CI) [M + H] + 379.

1- [N- (Diphenylmethyl) azetidinyl-3-oxy] -2-fluoro-4-aminobenzene

7.55 g (19.95 mmol) of 1- [N- (diphenylmethyl) azetidinyl-4-oxy] -2-fluoro-4-nitrobenzene, 7.31 g (116 mmol) of ammonium formate and about 250 mg of 10% Pd / C in 500 ml of MeOH at reflux for 21 h. After cooling, the reaction was filtered through a pad of Celite and methanol was evaporated, to obtain crude 1- [N- (diphenylmethyl) azetidinyl-3-oxy] -2-fluoro-4-aminobenzene as a yellow semisolid mustard. 1 H NMR (CDCl 3) δ 7.13-7.48 (m, 10H), 6.57 (t, J = 8.8 Hz, 1H), 6.43 (dd, J = 12.9, 2.6 Hz, 1H), 6.23-6.30 (m, 1H), 4.67-4.80 (m, 1H), 4.52 (s, 1H), 4, 00 (broad s, 2H), 3.73-3.85 (m, 2H), 3.13-3.23 (m, 2H). MS (CI) [M + H] + 349.

2-Fluoro-1- {N- (diphenylmethyl) azetidinyl-3-oxy} -4- (benzyloxycarbonylamino) benzene

Crude aniline (6.19 g, 17.77 mmol) was cooled in 750 ml of acetone / water (2: 1) at 0 ° C. 3.34 g (39.76 were added mmol) of sodium bicarbonate, followed by 3.3 ml (23.39 mmol) of Benzyl Chloroformate The reaction was stirred at temperature. ambient for 20 h and the volatiles were evaporated. The aqueous residue with 3 x 250 ml of EtOAc. The layers were dried combined organic over MgSO4, filtered and evaporated. Chromatography with 50% EtOAc / hexanes gave 2-fluoro-1- {N- (diphenylmethyl) azetidinyl-3-oxy} -4- (benzyloxycarbonylamino) benzene as a white solid; m.p. = 128-131 ° C; MS (CI) [M + H] + 483.

(R) - [3- [3-Fluoro-4- {N- (diphenylmethyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methanol

At 2.13 g (4.41 mmol) of 2-fluoro-1- {N- (diphenylmethyl) azetidinyl-3-oxy} -4- (benzyloxycarbonylamino) benzene in 75 ml of THF at -78 ° C under a nitrogen atmosphere , 2.5 ml of nBuLi (2.5 M in hexanes, 6.25 mmol) was added. The reaction was stirred for 0.5 h and then 0.65 ml of (R) -glycidyl butyrate (4.59 mmol) was added. The reaction was stirred at room temperature overnight, poured into 75 ml of saturated ammonium chloride (aq) and extracted with 3 x 100 ml of EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered and evaporated. Chromatography with 60% EtOAc / hexanes gave (R) - [3- [3-fluoro-4- {N- (diphenylmethyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methanol as a foam Dirty white. 1 H NMR (CDCl 3) δ 7.17-7.51 (m, 11H), 7.03 (d, J = 8.9 Hz, 1H), 6.70 (t, J = 8.9 Hz, 1H), 4.70-4.90 (m, 2H), 4.44 (s, 1H), 3.87-4.13 (m, 3H), 3.68-3, 76 (m, 3H), 3.13-3.18 (m, 2H), 2.05 (broad t, 1H). MS (CI) [M + H] + 449.

(S) - [3- [3-Fluoro-4- {N- (diphenylmethyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide

At 1.40 g (3.12 mmol) of (R) - [3- [3-fluoro-4- {N- (diphenylmethyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methanol and 0.90 ml (6.46 mmol) of TEA in 90 ml of CH2Cl2 at 0 ° C under a nitrogen atmosphere, 0.3 ml (3.87 mmol) of methanesulfonyl chloride was added. After stirring for 1.5 h, the reaction was poured into 150 ml of water and extracted. The aqueous layer was washed with an additional portion of CH2Cl2. The combined organic layers were dried over MgSO4, filtered and evaporated to obtain crude mesylate. MS (CI) [M + H] + 527. This mesylate (3.08 mmol) and 0.80 (12.31 mmol) of sodium azide in 75 ml of DMF were heated at 70 ° C for 2.5 hours under a nitrogen atmosphere. After cooling, the reaction was poured into 400 ml of water and extracted with 3 x 150 ml of EtOAc. The combined organic layers were washed with several portions of water, dried over MgSO4, filtered and evaporated to obtain (R) - [3- [3-fluoro-4- {N- (diphenylmethyl) azetidinyl-3 -oxy} phenyl] -2-oxo-5-oxazolidinyl] methylazide as a semi-solid. 1 H NMR (CDCl 3) δ 7.19-7.50 (m, 11H), 7.05 (d, J = 9.0 Hz, 1H), 6.74 (t, J = 9.0 Hz, 1H), 4.71-4.87 (m, 2H), 4.46 (s, 1H), 4.03 (t, J = 8.8 Hz, 1H), 3.50 -3.88 (m, 5H), 3.10-3.21 (m, 2H). MS [M + H] + 474.

(S) - [3- [3-Fluoro-4- {N- (diphenylmethyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide

1.13 g (2.39 mmol) of (R) - [3- [3-fluoro-4- {N- (diphenylmethyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] was stirred] methylazide and 0.85 g (3.24 mmol) of triphenylphosphine in 60 ml of THF at room temperature under a nitrogen atmosphere overnight. 3.0 ml of water was added and the reaction was heated at 70 ° C for 6 h. The volatiles were evaporated and the water was azeotroped with several portions of benzene, to obtain a mixture of crude amine and triphenylphosphine oxide. MS (CI) [M + H] + 448. The crude amine, 0.3 ml (3.17 mmol) of acetic anhydride and 0.6 ml (7.42 mmol) of pyridine in 75 ml were stirred of EtOAc at room temperature under a nitrogen atmosphere overnight. The reaction was extracted with 100 ml of water. The organic layer was dried over MgSO4, filtered and evaporated. Chromatography with 2% MeOH / CH2Cl2 gave (S) - [3- [3-fluoro-4- {N- (diphenylmethyl) azetidinyl-3-oxy} phenyl] -2-oxo-5 -oxazolidinyl] methylacetamide as a white foam. 1 H NMR (CDCl 3) δ 7.13-7.50 (m, 11H), 6.92-7.03 (m, 1H), 6.70 (t, J = 8, 9 Hz, 1H), 5.96 (broad s, 1H), 4.68-4.85 (m, 2H), 4.45 (s, 1H), 3.97 (t, J = 9.0 Hz , 1H), 3.50-3.76 (m, 5H), 3.10-3.19 (m, 2H), 2.03 (s, 3H). MS (CI) [M + H] + 490.

(S) -N - [[3- [3-Fluoro-4- {N- (methanesulfonyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (Compound 57)

At 160 mg (0.327 mmol) of (S) - [3- [3-fluoro-4- {N- (diphenylmethyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide in 5 ml of 1,2-dichloroethane 0.04 ml (0.371 mmol) of α-chloroethyl chloroformate was added. The reaction was heated at 70 ° C for 5 h. 10 ml of MeOH was added and reflux was continued overnight. Volatiles were evaporated to obtain the crude hydrochloride salt of the unprotected amine. This was suspended in 20 ml of CH2Cl2 and 0.15 ml (1.07 mmol) of TEA was added, followed by 0.1 ml (1.29 mmol) of methanesulfonyl chloride. The reaction was stirred overnight, poured into 100 ml of water and extracted. The organic layer was washed with 1 N HCl (aq.), Dried over MgSO4, filtered and evaporated. Chromatography with 3% MeOH / CH 2 Cl 2 gave (S) -N - [[3- [3-fluoro-4- {N- (methanesulfonyl) azetidinyl-3-oxy} phenyl] -2- oxo-5-oxazolidinyl] methyl] acetamide as a white foam. 1 H NMR (CDCl 3) δ 7.52 (dd, J = 13.1, 2.7 Hz, 1H), 7.06-7.10 (m, 1H), 6.76 (t, J = 8.9 Hz, 1H), 5.91 (broad t, 1H), 4.87-4.95 (m, 1H), 4.72-4.81 (m, 1H), 4 , 28 (dd, J = 9.7, 6.4 Hz, 2H), 4.09 (dd, J = 9.7, 4.8 Hz, 2H), 4.01 (t, J = 8.9 Hz, 1H), 3.56-3.77 (m, 3H), 2.93 (s, 3H), 2.02 (s, 3H). MS (CI) [M + H] + 402.

Example 58 (S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

75

258 mg (0.527 mmol) of (S) - [3- [3-Fluoro-4- {N- (diphenylmethyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide of Example 57 and 0.20 ml (1.26 mmol) of benzyloxyacetyl chloride in 10 ml of 1,2-dichloroethane at reflux for 48 h under an atmosphere of nitrogen. After cooling, the reaction with 100 ml of CH2Cl2 and extracted with 50 ml of 1N HCl. The organic layer was washed with water, dried over MgSO4, filtered and evaporated. Chromatography with MeOH 3% / CH 2 Cl 2 gave (S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) -azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide like a white powder; m.p. = 119-121 ° C; MS (CI) [M + H] + 472.

Example 59 (S) -N - [[3- [3-Fluoro-4- {N- (acetoxyacetyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

76

323 mg (0.660 mmol) of (S) - [3- [3-Fluoro-4- {N- (diphenylmethyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methylacetamide of Example 57 and 0.2 ml (1.86 mmol) of acetoxyacetyl chloride in 15 ml of 1,2-dichloroethane at reflux for 24 h. After cooling, volatiles were evaporated and chromatographed the residue with 3% MeOH / CH 2 Cl 2. It was isolated (S) -N - [[3- [3-Fluoro-4- {N- (acetoxyacetyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a white solid; m.p. = 172-175 ° C; MS (CI) [M + H] + 424.

Example 60 (S) -N - [[3- [3-Fluoro-4- {N- (acetoxyacetyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] -N - [α-acetoxyacetyl ] acetamide

77

This was also isolated (as a white foam) from the reaction mixture of Example 59. 1 H NMR (CDCl 3) δ 7.53 (dd, J = 13.0, 2.8 Hz, 1H), 7.04-7.10 (m, 1H), 6.78 (t, J = 8.8 Hz, 1H), 4.95-5.18 (m, 3H), 4.75 -4.89 (m, 1H), 4.30-4.68 (m, 5H), 4.00-4.30 (m, 3H), 3.83-3.91 (m, 1H), 3 , 68-3.79 (m, 1H), 2.47 (s, 3H), 2.02 (s, 3H), 2.18 (s, 3H). MS (CI) [M + Na] + 546.

Example 61 (S) -N - [[3- [3-Fluoro-4- {N - (α-hydroxyacetyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide

78

150 mg (0.354 mmol) of (S) -N - [[3- [3-fluoro-4- {N- (acetoxyacetyl) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl was stirred ] acetamide of Example 59 and 55 mg of potassium carbonate in 30 ml of MeOH at room temperature for 20 minutes under a nitrogen atmosphere. The volatiles were evaporated and the sample was dissolved in 50 ml of CH2Cl2. This was washed with 50 ml of water, dried over MgSO4, filtered and evaporated, to obtain (S) -N - [[3- [3-fluoro-4- {N - (α-hydroxyacetyl) ) azetidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide as a white solid; mp = 158-160 ° C; 1 H NMR (MeOH-d 4) δ 7.57 (dd, J = 13.3, 2.6 Hz, 1H), 7.15-7.18 (m, 1H), 6 , 91 (t, J = 9.0 Hz, 1H), 5.04-5.12 (m, 1H), 4.66-4.80 (m, 2H), 4.44 (dd, J = 10 , 6, 6.7 Hz, 1H), 4.27-4.34 (m, 1H), 4.01-4.11 (m, 4H), 3.78 (dd, J = 9.2, 6 , 4 Hz, 1H), 3.55 (d, J = 5.0 Hz, 2H), 1.96 (s, 3H). MS (CI) [M + H] + 382.

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The invention has been described in detail. making particular reference to the previous embodiments of the same. The above embodiments and examples are provided for illustrate the scope of the present invention. These realizations and examples will make it apparent to those skilled in the art other realizations and examples. These embodiments and examples are within the contemplation of the present invention. It will be understood that variations and modifications can be made in the scope of the invention; therefore, the present invention would be only limited by the appended claims.

Claims (11)

1. A compound of Formula I

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79 where R_ {1} is

         \ vskip1.000000 \ baselineskip
      

80

         \ vskip1.000000 \ baselineskip
      

where

(to)

R 3 is H, alkyl, COR 4, - (CH 2) heteroaryl, -CHR 5 R 6, - (CH 2) t aryl, -SO 2 NR 5 R 6 or -SO 2 R 9;

(b)

R 4 is H, -OR 5, alkyl, alkylaryl, - (CH 2) t aryl, - (CH 2) t heteroaryl, - (CH 2) t OR 5, - (CH 2) t NR 7 R 8, -CHR 5 R 6 or -NR5R6 that eventually forms an amino derivative cyclic;

(C)

R 5 and R 6 are independently H, alkyl, alkylaryl, haloaryl, - (CH 2) t aryl, - (CH 2) t -heteroaryl or acyl;

(d)

R 7 and R 8 are independently H, alkyl, -COR 9, -SO 2 R 9 or -CO_ {R} {9}, and

(and)

R 9 is H, alkyl, aryl and alkylaryl;

R2 is C (O) R9 or C (O) OR9; R 2a is H or acyl, with the proviso that, when R 3 is alkyl, - (CH 2) t aryl, - (CH 2) t heteroaryl or -CHR 5 R 6, R 2a let H; X is N or CH; Y is H, halogen, alkoxy or alkyl, and t is an integer from 0 to 4; or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a salt pharmaceutically acceptable thereof, where alkyl is alkyl C 1-8; heteroaryl is a cyclic aromatic radical of five to ten ring atoms, of which one ring atom is selected from S, O and N, 0-2 ring atoms are additional heteroatoms independently selected from S, O and N and the rest of the ring atoms are carbon; aryl is a carbocyclic aromatic radical selected from phenyl, 1-naphthyl or 2-naphthyl; acyl is an organic radical that has 2 to 6 carbon atoms derived from an organic acid by elimination of hydroxyl group, and alkoxy is an oxygen ether formed from I rent. 2. The compound of Claim 1, wherein X it's CH. 3. The compound of Claim 1, wherein R2 is -C (O) R9, where R9 is as defined in Claim-
tion 1. 4. The compound of Claim 3, wherein R 9 is H or alkyl. 5. The compound of Claim 1, wherein R_ {1} is 81 where R_ {3} is as it has been defined in the Claim one. 6. The compound of Claim 5, wherein R 2a is H and R 2 is -COR 4, -SO 2 R 9 or - (CH 2) t heteroaryl, where R 4, R 9 and t are as defined in claim 1. 7. The compound of Claim 5, wherein R4 is -OR 5, - (CH 2) t OR 5, alkyl- (CH2) t aryl or - (CH 2) t heteroaryl, where R 5 and t are as defined in claim 1. 8. The compound of Claim 7, wherein R 5 is alkyl and R 9 is H or alkyl. 9. A compound of Claim 1 or a salt pharmaceutically acceptable thereof, which is (S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide or (S) -N - [[3- [3-Fluoro-4- {N - (α-hydroxyacetyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide or (S) -N - [[3- [3-Fluoro-4- {N- (methanesulfonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide or (S) -N - [[3- [3-Fluoro-4- {N- (methoxycarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide or (S) -N - [[3- [3-Fluoro-4- {N- (2-pyrimidinyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide or (S) -N - [[3- [3-Fluoro-4- {N- (3-cyanobenzoyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide or (S) -N - [[3- [3-Fluoro-4- {N- (5-cyano-2-pyridyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide  or (S) -N - [[3- [3-Fluoro-4- {N- (2-thienylcarbonyl) piperidinyl-4-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide or (S) -N - [[3- [3-Fluoro-4- {N - (α-hydroxyacetyl) piperidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide  or (S) -N - [[3- [3-Fluoro-4- {N- (benzyloxyacetyl) pyrrolidinyl-3-oxy} phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide. 10. A pharmaceutical composition consisting of a compound of any one of claims 1 to 9 and a pharmaceutically acceptable support. 11. A compound of any one of Claims 1 to 9 or a composition of Claim 10 for use in the treatment of a subject having a condition caused by, or contributing to, a bacterial infection, or to prevent a subject from suffering of a condition caused by, or contributing to, a bacterial infection, such as community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, bone and joint infections and hospital lung infections, caused, for example, by a Gram positive coconut, a Gram positive coconut that is resistant to antibiotics, S. aureus, S. epidermidis, S. pneumonaie, Enterococcus spp. Moraxella catarrhalis or H. influenzae .